WO2017136642A1 - Compositions antibiotiques - Google Patents

Compositions antibiotiques Download PDF

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Publication number
WO2017136642A1
WO2017136642A1 PCT/US2017/016378 US2017016378W WO2017136642A1 WO 2017136642 A1 WO2017136642 A1 WO 2017136642A1 US 2017016378 W US2017016378 W US 2017016378W WO 2017136642 A1 WO2017136642 A1 WO 2017136642A1
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Prior art keywords
compound
formula
composition
pharmaceutically acceptable
acceptable salt
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PCT/US2017/016378
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English (en)
Inventor
Ambrose Lin Yau CHEUNG
Dhanalakshmi R. NAIR-SCHAEF
Jimmy Wu
Ji Chen
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The Trustees Of Dartmouth College
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Publication of WO2017136642A1 publication Critical patent/WO2017136642A1/fr

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Classifications

    • 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
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • MRSA Methicillin-resistant Staphylococcus aureus
  • composition comprising an antibiotic and a compound of formula (I), or a pharmaceutically acceptable salt thereof:
  • X is OR or NHR;
  • R is hydrogen or R 1 -R 2 -(R 3 ) n ;
  • R 1 is selected from C 1-6 alkyl, C 2-6 alkynyl, aryl and heteroaryl;
  • R 2 is selected from aryl and heteroaryl, or is absent;
  • each R 3 is independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 fluoroalkyl, C 1- 6 fluoroalkoxy, halogen, cyano and -CO 2 R 4 ;
  • R 4 is hydrogen or C 1-6 alkyl;
  • R 5 , R 6 , R 7 and R 8 are independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1- 6 fluoroalkyl and C 1-6 fluoroalkoxy; and
  • n is 0-3; provided that at least one of R 5 , R 6 , R 7 and R 8 is C 1-6 fluor
  • R 8 is C 1-6 fluoroalkoxy.
  • R5, R6 and R7 are hydrogen, and R8 is C1-6fluoroalkoxy.
  • R 8 is trifluoromethoxy.
  • the compound of formula (I) has the structure of formula (II), or a pharmaceutically acceptable salt thereof:
  • the compound of formula (II) has the structure of formula (IIa), or a pharmaceutically acceptable salt thereof:
  • the compound of formula (II) has the structure of formula (IIb), or a pharmaceutically acceptable salt thereof:
  • R 7 is C 1-6 fluoroalkyl.
  • R5, R6 and R8 are independently selected from hydrogen and C1- 6 fluoroalkyl.
  • R 5 , R 6 and R 8 are hydrogen.
  • R5 is C1-6fluoroalkyl and R6 and R8 are hydrogen.
  • said C 1-6 flouroalkyl is trifluoromethyl.
  • R7 is trifluoromethyl.
  • the compound of formula (I) has the structure of formula (III), or a pharmaceutically acceptable salt thereof:
  • the compound of formula (III) has the structure of formula (IIIa), or a pharmaceutically acceptable salt thereof:
  • he compound of formula (III) has the structure of formula (IIIb), or a pharmaceutically acceptable salt thereof:
  • R 6 is C 1-6 fluoroalkyl.
  • R5, R7 and R8 are independently selected from hydrogen and C1- 6 fluoroalkyl.
  • R 5 , R 7 and R 8 are hydrogen.
  • R6 is trifluoromethyl.
  • the compound of formula (I) has the structure of formula (IV), or a pharmaceutically acceptable salt thereof:
  • the compound of formula (IV) has the structure of formula (IVa), or a pharmaceutically acceptable salt thereof:
  • X is OR and the compound has the structure of formula (V), or a pharmaceutically acceptable salt thereof:
  • R is hydrogen and the compound of formula (V) has the structure of formula (Va), or a pharmaceutically acceptable salt thereof:
  • the compound of formula (Va) is selected from compounds (1), (1b), (1c), and (1f) of Table 1(a), and pharmaceutically acceptable salts thereof.
  • R is R 1 -R 2 - R 3 ; wherein R 1 is selected from C 1-6 alkyl, C 2-6 alkynyl, aryl and heteroaryl; R 2 is heteroaryl; R 3 is -CO 2 H or -CO 2 C 1-6 ; and n is 1.
  • R 2 is selected from furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, and thiadiazolyl.
  • R 2 is isoxazol-3-yl.
  • the compound of formula (V) has the structure of formula (Va):
  • the compound of formula (Va) has the structure of formula (Vb), or a pharmaceutically acceptable salt thereof:
  • the compound of formula (Va) has the structure of formula (Vc), or a pharmaceutically acceptable salt thereof:
  • R 3 is -CO 2 H or -CO 2 CH 2 CH 3 .
  • X is NHR and the compound of formula (I) has the structure of formula (VI):
  • R is R 1 -R 2 -R 3 ;
  • R 1 is aryl or heteroaryl;
  • R 2 is absent; and each R 3 is independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 fluoroalkyl, C 1-6 fluoroalkoxy, halogen and cyano.
  • R 1 is phenyl.
  • the compound has the structure of formula (VII):
  • R 6 is hydrogen and R 5 , R 7 and R 8 are
  • the compound of formula (VII) has the structure of formula (VIIa):
  • the compound of formula (VII) has the structure of formula (VIIb)
  • R 3 is trifluoromethyl and n is 0 or 1.
  • the compound of formula (VII) is selected from compounds (3a) and (3b) of Table 1(b), and pharmaceutically acceptable salts thereof.
  • the antibiotic is selected from cefoxitin, nafcillin and oxacillin.
  • antibiotic is cefoxitin.
  • the antibiotic is cefoxitin and the compound is compound (1), or a pharmaceutically acceptable salt thereof.
  • the antibiotic is cefoxitin and the compound is compound (1b), or a pharmaceutically acceptable salt thereof.
  • the antibiotic is nafcillin.
  • the antibiotic is nafcillin and the compound is compound (1b), or a pharmaceutically acceptable salt thereof.
  • the antibiotic is oxacillin.
  • the antibiotic is oxacillin and the compound is compound (1), or a pharmaceutically acceptable salt thereof.
  • the antibiotic is oxacillin and the compound is compound (1b),
  • the antibiotic is oxacillin and the compound is compound (1c), or a pharmaceutically acceptable salt thereof.
  • the antibiotic is oxacillin and the compound is compound (1f), or a pharmaceutically acceptable salt thereof.
  • the antibiotic is oxacillin and the compound is compound (3a), or a pharmaceutically acceptable salt thereof.
  • the antibiotic is oxacillin and the compound is compound (3b), or a pharmaceutically acceptable salt thereof.
  • a method of treating or preventing a bacterial infection a subject in need thereof comprising administering to the subject a therapeutically-effective amount of the composition comprising a compound of formula (I) (for example, compounds of formulas (II)-(VII)) and an antibiotic.
  • a compound of formula (I) for example, compounds of formulas (II)-(VII)
  • the method comprises the steps of: (a) administering to the subject a compound of formula (I) (including, for example, compounds of formulas (II)-(VII)); and (b) administering to the subject a therapeutically- effective amount of an antibiotic.
  • the method comprises the steps of: (a) administering to the subject a therapeutically-effective amount of an antibiotic; and (b) administering to the subject a compound of formula (I) (for example, compounds of formulas (II)-(VII)).
  • a method of treating or preventing a bacterial infection a subject in need thereof comprising administering to the subject a therapeutically-effective amount of the composition described herein.
  • the method comprises the steps of: (a) administering to the subject a compound of formula (I) (for example, compounds of formulas (II)-(VII)); and (b) administering to the subject a therapeutically-effective amount of an antibiotic selected from cefoxitin, nafcillin and oxacillin.
  • a compound of formula (I) for example, compounds of formulas (II)-(VII)
  • an antibiotic selected from cefoxitin, nafcillin and oxacillin.
  • the method comprises the steps of: (a) administering to the subject a therapeutically-effective amount of an antibiotic selected from cefoxitin, nafcillin and oxacillin; and (b) administering to the subject a compound of formula (I) (for example, compounds of formulas (II)-(VII)).
  • the antibiotic is oxacillin.
  • the compound is selected from the group of compounds (1), (1b), (1c), (1f), (3a), (3b), and
  • the bacterial infection is caused by a gram positive bacterium.
  • the gram positive bacterium is selected from Staphylococcus aureus, Staphylococcus epidermidis,
  • the bacterial infection is caused by Staphylococcus aureus. In another particular embodiment, the bacterial infection is caused by methicillin-resistant Staphylococcus aureus. In another particular embodiment,
  • the methicillin-resistant Staphylococcus aureus is a community- acquired strain.
  • the methicillin-resistant Staphylococcus aureus is a community- acquired strain.
  • Staphylococcus aureus is a hospital-acquired strain.
  • the bacterial infection is caused by the USA300 strain of methicillin-resistant
  • R is R 1 -R 2 -(R 3 ) n ;
  • R 1 is aryl or heteroaryl;
  • R 2 is absent;
  • each R 3 is independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 fluoroalkyl, C 1-6 fluoroalkoxy, halogen and cyano;
  • R 5 , R 6 , R 7 and R 8 are independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 fluoroalkyl and C 1-6 fluoroalkoxy; and
  • n is 0-3.
  • R 5 , R 6 , R 7 and R 8 is C 1-6 fluoroalkyl or C 1-6 fluoroalkoxy. In another embodiment, R 8 is C 1-6 fluoroalkoxy. In still another embodiment, R 5 , R 6 and R 7 are hydrogen, and R 8 is C 1-6 fluoroalkoxy. In a particular embodiment, R 8 is trifluoromethoxy.
  • the compound of formula (VI) has the structure of formula (VIa):
  • the compound of formula (VIa) has the structure of formula (VIb), or a pharmaceutically acceptable salt thereof:
  • R 7 is C 1- 6 fluoroalkyl.
  • R 5 , R 6 and R 8 are independently selected from hydrogen and C 1-6 fluoroalkyl.
  • R 5 , R 6 and R 8 are hydrogen.
  • R 5 is C 1-6 fluoroalkyl and R 6 and R 8 are hydrogen.
  • said C 1-6 flouroalkyl is trifluoromethyl.
  • R 7 is trifluoromethyl and the compound of formula (VI) has the structure of formula (VIc):
  • the compound of formula (VIc) has the structure of formula (VId):
  • the compound of formula (VIc) has the structure of formula (VIe):
  • R 6 is C 1- 6 fluoroalkyl.
  • R 5 , R 7 and R 8 are independently selected from hydrogen and C 1-6 fluoroalkyl.
  • R 5 , R 7 and R 8 are hydrogen.
  • R 6 is trifluoromethyl.
  • the compound of formula (VI) has the structure of formula (VIf), or a pharmaceutically acceptable salt thereof: (VIf).
  • the compound of formula (VIf) has the structure of formula (VIg), or a pharmaceutically acceptable salt thereof:
  • the compound of formula (VI) has the structure of formula (VII):
  • R 6 is hydrogen and R 5 , R 7 and R 8 are independently selected from hydrogen, C 1-6 fluoroalkyl and C 1- 6 fluoroalkoxy.
  • the compound of formula (VII) has the structure of formula (VIIa):
  • the compound of formula (VII) has the structure of formula (VIIb):
  • R 3 is trifluoromethyl and n is 0 or 1.
  • the compound is selected from compounds (3a) and (3b), and pharmaceutically acceptable salts thereof.
  • the compound is compound (3a), or a pharmaceutically acceptable salt thereof.
  • the compound is compound (3b), or a pharmaceutically acceptable salt thereof.
  • FIG.1 depicts time kill curves of MRSA USA300 with different concentrations of compound 1.
  • USA300 cells were grown to mid-log phase, back diluted 100-fold and treated with (a) 0.5X compound 1 (open circle), 1X compound 1 (closed square), 2X compound 1 (open square) and 4X MIC of compound 1 (closed triangle) or left untreated (closed circle). Samples were taken at 0, 2, 4, 6 and 24 hrs and a viable count carried out.
  • Asterisk denotes P values of ⁇ 0.05 as determined by Tukey"s multiple comparison test of two way analysis of variance. The lines show the mean and SE.
  • FIG.2 depicts time kill curves of MRSA USA300 with different concentrations of compound 1b.
  • USA300 cells were grown to mid-log phase, back diluted 100-fold and treated with 0.125X MIC (open circle), 0.25X MIC (open square), 0.5X MIC (closed square) and 1X MIC of compound 1b (closed triangle) or left untreated (closed circle). Samples were taken at 0, 2, 4, 6 and 24 hrs and a viable count carried out.
  • Asterisk denotes P values of ⁇ 0.05 as determined by Tukey"s multiple comparison test of two way analysis of variance. The lines show the mean and SE.
  • FIG.3 depicts percent inhibition of macromolecular biosynthesis of Staphylococcus simulans 22 by compound 1 as measured by inhibition of radiolabeled precursor incorporation into nascent DNA (open square), RNA (open circle),
  • peptidoglycan (closed circle) and protein (closed square). Bacteria were treated with compound 1 for 30 minutes in the presence of radioactive precursors. The data are presented as percent inhibition compared to control with no antibiotic.
  • FIG.4 depicts percent inhibition of DNA biosynthesis of S. simulans 22 by compound 1: 0.5X MIC (open square), 1X MIC (closed square), 2X MIC (open triangle) of compound 1 normalized to control with no antibiotic, over a period of time. Control with no antibiotic is denoted by open circle and ciprofloxacin (10X MIC) (closed circle) was used as a positive control.
  • FIG.5 depicts percent inhibition of cell wall biosynthesis of S.
  • FIG.6 depicts control cells and compound 1 treated cells, shown at 1200X magnification, showing the effect of compound 1 on cell wall by TEM. USA300 cells were grown to mid-log phase and treated with compound 1 for 90 minutes, or left untreated (control). Cells were then collected and processed for EM as described in Material and Methods.
  • FIG.7 depicts the effect of compound 1 on cell wall by
  • FIG.8 depicts the effect of compound 1 on cell wall by
  • FIG.9 depicts the effect of compound 1 on cell wall by
  • TEM TEM. USA300 cells were grown to mid-log phase and treated with compound 1 for 90 minutes, or left untreated (control). Cells were then collected and processed for EM as described in Material and Methods. Mesosome-like invaginations are seen both along the cell wall and along the septum in cells at 15000X magnification (arrows, right panel).
  • FIG.10 depicts microscopy showing activation of the vraRS cell wall stress stimulon using strains containing a vraRS promoter driving sfGFP expression.
  • *p value ⁇ 0.0001 between DMSO control and vancomycin-treated cells and ⁇ 0.05 between control and compound 1 treated cells.
  • FIG.11 depicts microscopy showing localization of PBP2 and FtsZ by compound 1. Localization of the PBP2 and FtsZ was tracked using strains expressing GFP-PBP2 or FtsZ-CFP after treatment with 1x MIC compound 1 for 30 min.
  • FIG.12 depicts microscopy showing the disruption of cell membrane and depolarization by compound 1. Cells were either untreated (control) or treated with 1X MIC compound 1 for 30 min and stained with FM 4-64 to visualize the membrane, Van-FL to visualize the cell wall (middle panels) or Hoechst 33342 to stain the DNA.
  • FIG.13 depicts a graph showing the disruption of cell membrane and depolarization by compound 1. Actively growing USA300 cells were back-diluted, resuspended in PBS with glucose and treated with DiOC 2 in the dark for 30 minutes at 25°C. Loss in fluorescence was monitored over time upon adding increasing
  • FIG.14 depicts the effects of compound 1, alone and in combination with oxacillin, against strains of community-acquired MRSA (CA-MRSA) and hospital- acquired MRSA (HA-MRSA). DETAILED DESCRIPTION
  • compositions of the invention refers to one or more compounds of the invention in combination with one or more antibiotics, as described herein.
  • compounds of the invention affect the cell wall.
  • compound 1 is effective on its own against a variety MRSA strains, and is synergistic with -lactams such as oxacillin and cefoxitin. Evaluation of the pharmacokinetic and toxicity profiles of compound 1 show that it is stable in human microsomes, is cell permeable and does not exhibit any major cytotoxicity.
  • compound 1b is only as active as compound 1 on its own, but its activity in combination with oxacillin is 10 fold better than compound 1.
  • Analogues of compound 1 in which the hydroxyl group was modified were also examined. Alkylation of the 4-hydroxy group with either a propargyl group or isoxazole completely neutralized the antimicrobial activity of compound 2a i as shown in Table 1(b). This observation suggests that a hydrogen bond donor moiety in that region of the molecule may be required for antimicrobial activity.
  • hydrolysis of compound 2i to yield a carboxylic acid moiety in compound 2j recovered the activity to the level of compound 1c from which compound 2j is derived.
  • compounds 3a and 3b which are both hydrogen bond donors, exhibit good activity against MRSA with oxacillin. These observations may also indicate a correlation between hydrogen bond donors and antimicrobial activity.
  • a direct target was not immediately apparent.
  • the effect of compound 1 was monitored over time in macromolecular synthesis assays. In these assays, compound 1 was most efficient in inhibiting DNA and cell wall synthesis in a concentration dependent manner and transcription to a lesser degree. Similar macromolecular assays have shown that other inhibitors of DNA replication behave differently from each other.
  • ciprofloxacin exhibits a rapid concentration dependent inhibition of DNA synthesis in 30 min, however, novobiocin exerts effects on both DNA and RNA synthesis in the same time frame. Neither of these drugs had any effect on cell wall synthesis either directly or indirectly. In contrast, the inhibitory effect of compound 1 on cell wall synthesis, occurring within 30 minutes of exposure, is concentration dependent.
  • Activation of the vraRS system is a reliable way to assess cell wall stress.
  • the effect of compound 1 on the cell wall was confirmed using a vraRS promoter fusion to GFP.
  • Treatment with compound 1 showed a significant activation of the cell- wall stress response operon, albeit to lower level compared to vancomycin.
  • Kuroda et al. have previously shown that treatment of cells with levofloxacin, unlike cell-wall active compounds, does not induce transcription of vraRS. This induction is thus a specific cell- wall stress response, as general stresses like heat, high osmolarity and pH shift do not appear to affect vraRS transcription thus indicating that this is not likely to be a secondary affect due to growth inhibition.
  • mislocalization of FtsZ as a cause of the PBP2 defect in the cell wall.
  • the mislocalization of PBP2 points to impairment in peptidoglycan synthesis at the cross wall.
  • Bactericidal activity by way of inhibiting cell wall synthesis is generally a slow process, and the time kill assay mirrors this temporal requirement.
  • composition may also refer to a
  • composition is defined herein to refer to a mixture or solution containing at least one therapeutic agent to be administered to a subject, e.g., a mammal or human, in order to prevent or treat a particular disease or condition affecting the mammal or human.
  • pharmaceutically acceptable is defined herein to refer to those compounds, materials, compositions and/or dosage forms, which are, within the scope of sound medical judgment, suitable for contact with the tissues a subject, e.g., a mammal or human, without excessive toxicity, irritation allergic response and other problem complications commensurate with a reasonable benefit / risk ratio.
  • treating comprises a treatment relieving, reducing or alleviating at least one symptom in a subject or effecting a delay of progression of a disease.
  • treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a disorder, such as cancer.
  • the term “treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.
  • prevent means the prevention of at least one symptom associated with or caused by the state, disease or disorder being prevented.
  • terapéuticaally effective amount of a compound or combination of the invention is an amount of the compound, combination, or a constituent of a combination sufficient to provide an observable improvement over the baseline clinically observable signs and symptoms of the disorder treated with the combination.
  • administering or “administration” and the like, refers to providing the compound or combination of the invention to the subject in need of treatment.
  • alkyl refers to a fully saturated branched or unbranched hydrocarbon moiety.
  • the alkyl can comprise 1 to 20 carbon atoms, 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbons, 1 to 4 carbons, or 1 to 3 carbon atoms.
  • the alkyl comprises 1-6 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n- nonyl, n-decyl and the like.
  • C x-y -alkyl indicates a particular alkyl group (straight- or branched-chain) of a particular range of carbons.
  • C 1 - 4 alkyl includes, but is not limited to, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl and isobutyl.
  • alkyl may be understood to represent a monovalent radical (e.g., methyl), a divalent radical (e.g., methylene), or a trivalent radical (e.g., methane).
  • alkenyl refers to a straight-chain, cyclic or branched hydrocarbon residue comprising at least one carbon-carbon double bond (i.e., an olefinic bond) and the indicated number of carbon atoms.
  • Alkenyl groups may have up to 8, up to 6, particularly up to 4, and more particularly up to 2 carbon atoms. Examples of alkenyl groups are ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3- butenyl, isobutenyl, 1-cyclohexenyl, 1-cyclopentenyl.
  • alkenyl may be understood to represent a monovalent radical, a divalent radical, or a trivalent radical.
  • alkynyl refers to a straight-chain or branched hydrocarbon residue comprising at least one triple carbon-carbon bond and the indicated number of carbon atoms.
  • Alkynyl groups may comprise 2 to 20 carbon atoms, 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 7 carbon atoms, 2 to 6 carbons, 2 to 4 carbons, or 2 to 3 carbon atoms.
  • the alkynyl group is a C 2 - 6 alkynyl group.
  • Non-limiting examples of alkynyl groups are ethynyl and propargyl.
  • the term "alkynyl" may be understood to represent a monovalent radical or a divalent radical.
  • aryl refers to aromatic monocyclic or multicyclic, e.g., bicyclic and tricyclic, hydrocarbon ring systems, consisting only of hydrogen and carbon and containing from 6-20 carbon atoms, or 6-10 carbon atoms, particularly 6 carbon atoms, where the ring systems may be partially saturated.
  • Aryl groups include, but are not limited to, groups such as phenyl, tolyl, xylyl, anthryl, naphthyl and phenanthryl.
  • Aryl groups can also be fused or bridged with alicyclic or heterocyclic rings which are not aromatic so as to form a polycycle (e.g., tetralin).
  • aryl may be understood to represent a monovalent radical (e.g., -C 6 H 5 ), a divalent radical (e.g., -C 6 H 4 -), or a trivalent, tetravalent, or pentavalent radical.
  • heteroaryl refers to a stable monocyclic or bicyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S.
  • Heteroaryl groups within the scope of this definition include but are not limited to: acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,
  • heteroaryl is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl.
  • heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively.
  • heteroaryl may be understood to represent a monovalent radical (e.g., -C4H3O), a divalent radical (e.g., - C 4 H 2 O-), or a higher order radical.
  • alkoxy refers to an alkyl groups, having from 1 to 10 carbon atoms, attached to the remainder of the molecule via an oxygen atom. Alkoxy groups may have 1-8 carbon atoms, 1-6 carbon atoms, 1-4 carbon atoms, 1-2 carbon atoms, or 1 carbon atom.
  • the alkyl portion of an alkoxy group may be linear, cyclic, or branched, or a combination thereof. Examples of alkoxy groups include methoxy, ethoxy, isopropoxy, butoxy, cyclopentyloxy, and the like.
  • An alkoxy group can also be represented by the following formula: -OR i , where R i is the "alkyl portion" of an alkoxy group.
  • halogen and “halo” refer to a fluorine, chlorine, bromine, or iodine atom.
  • fluoroalkyl are meant to include monofluoroalkyl and perfluoroalkyl.
  • C 1 ⁇ 6 fluoroalkyl is meant to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, and the like.
  • fluoroalkyl include -CF 3 , and -CF 2 CF 3 .
  • fluoroalkoxy are meant to include monofluoroalkoxy and perfluoroalkoxy.
  • cyano refers to the "CN moiety, wherein the carbon and nitrogen are connected by a triple bond. Molecules and molecular fragments comprising a cyano group may be referred to as nitriles.
  • alkyl, alkenyl, alkoxy, aryl and heteroaryl groups described above can be "unsubstituted” or “substituted.”
  • substituted is intended to describe moieties having substituents replacing a hydrogen on one or more atoms, e.g. C, O or N, of a molecule.
  • substituents can independently include, for example, one or more of the following: straight or branched alkyl (preferably C 1 -C 5 ), cycloalkyl (preferably C 3 -C 8 ), alkoxy (preferably C 1 -C 6 ), thioalkyl (preferably C 1 -C 6 ), alkenyl (preferably C 2 -C 6 ), alkynyl (preferably C 2 -C 6 ), heterocyclic, carbocyclic, aryl (e.g., phenyl), aryloxy (e.g., phenoxy), aralkyl (e.g., benzyl), aryloxyalkyl (e.g., phenyloxyalkyl),
  • the compounds of this invention may include asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers, stereoisomers, rotamers, tautomers, diastereomers, or racemates) are included within the scope of this invention. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. Furthermore, the structures and other compounds and moieties discussed in this application also include all tautomers thereof. Compounds described herein may be obtained through art recognized synthesis strategies.
  • substituents of some of the compounds of this invention include isomeric cyclic structures. It is to be understood accordingly that constitutional isomers of particular substituents are included within the scope of this invention, unless indicated otherwise.
  • tetrazole includes tetrazole, 2H-tetrazole, 3H-tetrazole, 4H-tetrazole and 5H-tetrazole.
  • the salts of the compounds described herein include acid addition salts and base addition salts.
  • the salt is a pharmaceutically acceptable salt of the compound of Formula I.
  • pharmaceutically acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention may be prepared from an inorganic acid or an organic acid.
  • inorganic acids include, without limitation, hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • organic acids may be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include, without limitation, formic, acetic, propionic, succinic, glycolic, gluconic, maleic, embonic (pamoic), methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic,
  • Suitable pharmaceutically-acceptable base addition salts of compounds of the invention include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, lysine and procaine. All of these salts may be prepared by conventional means from the corresponding compound of the invention by treating, for example, the compound of the invention with the appropriate acid or base.
  • compositions described herein can be administered to a system comprising cells or tissues, as well as to a human subject (e.g., a patient) or an animal subject.
  • compositions of the present invention can be administered in various dosage forms and strength, in a pharmaceutically effective amount or a clinically effective amount.
  • a composition described herein may be referred to as a "combination.”
  • a composition described herein may be referred to as a "pharmaceutical composition.”
  • compositions for separate administration of both combination components, or for the administration in a fixed combination, e.g., a single galenical composition comprising the combination may be prepared in any manner known in the art and are those suitable for enteral, such as oral or rectal, and parenteral administration to mammals (warm-blooded animals), including humans.
  • compositions described herein may contain, from about 0.1 % to about 99.9%, preferably from about 1 % to about 60 %, of the therapeutic agent(s).
  • Suitable pharmaceutical compositions for the combination therapy for enteral or parenteral administration are, for example, those in unit dosage forms, such as sugar- coated tablets, tablets, capsules or suppositories, or ampoules. If not indicated otherwise, these are prepared in a manner known per se, for example by means of various conventional mixing, comminution, direct compression, granulating, sugar-coating, dissolving, lyophilizing processes, or fabrication techniques readily apparent to those skilled in the art. It will be appreciated that the unit content of a combination partner contained in an individual dose of each dosage form need not in itself constitute an effective amount since the necessary effective amount may be reached by administration of a plurality of dosage units.
  • the unit dosage forms of the present invention may optionally further comprise additional conventional carriers or excipients used for
  • Such carriers include, but are not limited to, disintegrants, binders, lubricants, glidants, stabilizers, and fillers, diluents, colorants, flavors and preservatives.
  • disintegrants include, but are not limited to, disintegrants, binders, lubricants, glidants, stabilizers, and fillers, diluents, colorants, flavors and preservatives.
  • the term "pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp.1289- 1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
  • each combination partner for treatment of a bacterial infection can be determined empirically for each individual using known methods and will depend upon a variety of factors, including, though not limited to, the degree of advancement of the disease; the age, body weight, general health, gender and diet of the individual; the time and route of administration; and other medications the individual is taking. Optimal dosages may be established using routine testing and procedures that are well known in the art.
  • each combination partner that may be combined with the carrier materials to produce a single dosage form will vary depending upon the individual treated and the particular mode of administration.
  • the unit dosage forms containing the combination of agents as described herein will contain the amounts of each agent of the combination that are typically administered when the agents are administered alone.
  • each of the combination partners employed in the combination of the invention may vary depending on the particular compound or pharmaceutical composition employed, the mode of administration, the condition being treated, and the severity of the condition being treated.
  • the dosage regimen of the combinations described herein are selected in accordance with a variety of factors including the route of administration and the renal and hepatic function of the patient.
  • packaged pharmaceutical products may contain one or more dosage forms that contain the combination of compounds, and one or more dosage forms that contain one of the combination of compounds, but not the other compound(s) of the combination.
  • Bacterial strains, strain construction and media The strain used for compound screening was MRSA USA300, a community acquired MRSA strain. Also evaluated were clinical isolates of MRSA [Community-Acquired MRSA (20 strains), Hospital-Acquired MRSA (9 strains)] obtained from the Dartmouth Hitchcock Medical Centre, Lebanon NH for MIC studies (See FIG.14). The bacterial cells were grown in Mueller Hinton Broth (Difco) supplemented with calcium sulphate (50mg/L) and magnesium sulphate (25mg/L) (MHC) for MIC studies and in Tryptone Soy broth (TSB) (Difco) for growth.
  • MRSA COL was used for assessing membrane integrity, permeability and cell wall integrity by fluorescence microscopy.
  • MRSA strain BCBAJ020, a COL derivative expressing FtsZ-CFP ectopically from the spa locus under the control of the Pspac promoter was induced with 0.5mM IPTG.
  • MRSA strain COLpPvra expressing sfGFP under the control of the promoter of the vraRS operon, was used to evaluate activation of the cell wall stress response.
  • MIC by broth Microdilution and Macrodilution The MIC of compound 1 and compound 1b was determined with USA300 and other MRSA strains with and without sub-MIC oxacillin according to CLSI guidelines. The MIC is defined as the lowest concentration of antibiotic inhibiting visible bacterial growth.
  • Example 1 Determination of time kill curves using of compound 1 and compound 1b
  • FICAB was defined as the FIC
  • FIC BA was defined as the FIC of drug B in the presence of drug A, with FIC index (FICI) defined as FIC AB / FIC BA .
  • FICI FIC index
  • Synergy was defined as a FICI of less than or equal to 0.5, an index between 0.5 and 4 suggests indifference (no interaction) and an index of greater that 4 is antagonistic.
  • CFBE cells were maintained in RPMI 1640 medium (Sigma, St Louis MO) with 10% fetal bovine serum and grown with 5% CO 2 in an incubator at 37 °C. When confluent, cells in the flask were released with trypsin, collected and counted. Compound 1 at pre-determined
  • cytochrome P450 cytochrome P450
  • compound 1 was incubated with a cocktail of model CYP substrates specific for different CYP isoforms (phenactein for 1A2, bupropion for 2B6, diflofenac for 2C9, mepehenytoin for 2C19, bufuralol for 2D6, testosterone and midazolam for 3A4), human liver microsomes and cofactors for 20 minutes at 37 oC.
  • Specific control inhibitors for different CYP isoforms furafylline, thioTEPA.
  • Bidirectional permeability of compound 1 into Caco-2 cells was determined as follows: A CacoReady ⁇ plate (consisting of Caco-2 cells already plated on a HTS Transwell® 24-well plate) was purchased from ADMEcell Inc. (Emeryville, CA). On the day of the experiment, compound 1 was prepared in transport buffer (pHs 6.0 and 7.4) and added to the appropriate compartment (apical or basal) of the Transwell plate. At selected time points (0.5, 1, 1.5 and 2 hours), aliquots were removed from the receiving compartment and analyzed by LC-MS/MS to determine the apparent permeability (Papp, x 10 -6 cm/sec).
  • ketoconazole a known inhibitor of the transporter protein P-gp.
  • ER ⁇ 2 or that is significantly reduced in the presence of inhibitor further confirms that the compound 1 is a substrate for P-gp.
  • the % recovery of the test article was also determined. This was calculated by comparing the amount of compound 1 recovered during and at the end of the experiment with the amount of compound 1 added to initiate the experiment. Plasma protein binding to compound 1 was determined by equilibrium dialysis for 4 hrs at 37 oC using pooled human, Sprague Dawley rat, Beagle dog and BALB/C mouse plasma proteins.
  • Example 5 Enhanced efficacy of microbicidal activity of compound 1b compared to compound 1 on MRSA strain USA300
  • analogue compound 1b exhibits the same MIC as compound 1 against MRSA USA300, but is more efficient than compound 1 in time-kill experiments with almost complete bactericidal activity.
  • Example 6 Compound 1 and compound 1b are synergistic with cell-wall active antibiotics against MRSA, but are indifferent or antagonistic with other classes of drugs
  • Compound 1 was shown to be more potent against USA300 in the presence of sub-MIC oxacillin (Table 1). Specifically, compound 1b was shown to be ten- fold more potent in combination with sub-MIC oxacillin.
  • compound 1 or compound 1b can potentiate the activity of other classes of antibiotics, we investigated the effect of compound 1 and compound 1b on MRSA USA300 with other commonly used antibiotics including cell wall active agents (oxacillin, nafcillin, cloxacillin, cephalothin, cefoxitin, and vancomycin), an inhibitor of protein synthesis
  • Cultures were then split into aliquots, diluted to an OD 600 of 0.1 and allowed to regrow to an OD 600 of 0.4. Subsequently, the respective labelled precursor was added to each culture (final concentration 1 Ci/ml); compound was added at 0.5X , 1X or 2X MIC, while another aliquot was run with 10X MIC of a control antibiotic and one without any antibiotic.
  • Control antibiotics were vancomycin (3.1 mg/L) to inhibit cell wall synthesis, tetracycline (0.4 mg/L) to inhibit protein synthesis, ciprofloxacin (0.3mg/L) to inhibit DNA synthesis and rifampicin (0.01 ⁇ g/ml) to inhibit RNA synthesis.
  • USA300 cells grown in MHC at 37 C were treated with either compound 1 (2X MIC) or DMSO for 90 minutes.
  • the cells were washed twice with phosphate buffered saline (PBS) and processed for EM by fixing with 10X volume of 2% glutaraldehyde-tannic acid (GTA)/1% paraformaldehyde in 0.1M Na Cacodylate buffer (pH 7.4) .
  • Cells were further post-fixed in 1% OsO 4 in sodium cacodylate buffer pH 7.4, embedded and serially dehydrated in ethanol. Samples were sectioned and stained with uranyl acetate and imaged using a JEOL TEM 1010 microscope at 100kV at 1200X or 15,000X magnification.
  • CoolSNAP HQ2 camera Roper Scientific
  • Metamorph 7.5 software Molecular Devices
  • SIM Structured Illumination Microscopy
  • ELYRA PS.1 Microscope Zeiss
  • SIM images were reconstructed and analyzed with Zen Software
  • Compound 1 (8-(trifluoromethoxy)-2-(trifluoromethyl)quinolin-4-ol) shows an MIC of 8 mg/L against MRSA USA300.
  • the MIC of oxacillin against USA300 shows a 4-fold reduction from 128 mg/L to 32 mg/L in the presence of 4 mg/L of compound 1.
  • the MIC of compound 1 against a variety of CA-MRSA (20 strains) and HA-MRSA (8 strains) was in the range between 4-8 mgs/L and showed a 2-8 fold reduction in the presence of sub-MIC (16 mg/L) oxacillin (See Figure 14).
  • Example 12 Assessing toxicity of compound 1
  • the intrinsic clearance (CLint) of 1 ⁇ M of compound 1 was 2.2, 2.8, 8.4 and 35.4 ⁇ l/min/mg, respectively, for human, rat, dog and mouse liver microsomes; these data are consistent with a reasonable level of stability for compound 1 in human, rat and dog liver microsomes, but compound 1 is rapidly cleared in mouse liver microsomes, with a half- life of 39 min and an intrinsic clearance of 35.4 ⁇ l/min/mg.
  • Example 16 compound 1 causes activation of cell wall stress stimulon (CWSS) and mislocalization of PBP2 without affecting PBP4 and FtsZ
  • Cell wall active antibiotics are known to activate the cell wall stress stimulon. 14 Using a previously constructed COL strain (see Nair DR, Monteiro JM, Memmi G, et al. Characterization of a novel small molecule that potentiates beta-lactam activity against gram-positive and gram-negative pathogens. Antimicrob Agents
  • FtsZ is known to play a role in the localization of PBP2 to the septum in dividing cells.
  • a S. aureus strain containing CFP tagged with FtsZ was exposed to 0.5X- 2X MIC of compound 1 for 15 minutes ( Figure 5, right panels).
  • Example 17 Example 17: compound 1 has a concentration independent effect on the membrane of MRSA
  • the solution was filtered and the residue was washed with water and cold ethanol, then dried in vacuo to yield the crude 4-hydroxyquinoline.
  • the solution could be extracted with CHCl3 (20 mL x 3) and dried over anhydrous Na2SO4. After filtration, the solvent was removed in vacuo to give the crude 4-hydroxyquinoline. Then the residue was purified by column chromatography using hexane"EtOAc as an eluent (30% of EtOAc) to give the desired products with yields ranging from 45% to 60%.

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Abstract

La présente invention concerne des composés ayant une activité antimicrobienne, des compositions comprenant ces composés combinés à des antibiotiques bêta-lactamines, ainsi que des méthodes d'utilisation des composés et compositions.
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CN113620874A (zh) * 2021-08-10 2021-11-09 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) 2-三氟甲基-4-氨基-喹啉衍生物及其用途

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CN113620874A (zh) * 2021-08-10 2021-11-09 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) 2-三氟甲基-4-氨基-喹啉衍生物及其用途
CN113620874B (zh) * 2021-08-10 2024-02-06 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) 2-三氟甲基-4-氨基-喹啉衍生物及其用途

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