WO2016023106A1 - Alcaloïdes bis-indoliques destinés à être utilisés dans le traitement d'infections - Google Patents

Alcaloïdes bis-indoliques destinés à être utilisés dans le traitement d'infections Download PDF

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Publication number
WO2016023106A1
WO2016023106A1 PCT/CA2015/000468 CA2015000468W WO2016023106A1 WO 2016023106 A1 WO2016023106 A1 WO 2016023106A1 CA 2015000468 W CA2015000468 W CA 2015000468W WO 2016023106 A1 WO2016023106 A1 WO 2016023106A1
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Prior art keywords
infection
compound
mrsa
nmr
mhz
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PCT/CA2015/000468
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English (en)
Inventor
Raymond J. Andersen
Neil E. Reiner
Roya Zoraghi
Wendy K. STRANGMAN
Tina BOTT
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The University Of British Columbia
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Publication of WO2016023106A1 publication Critical patent/WO2016023106A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/582—Recycling of unreacted starting or intermediate materials

Definitions

  • This invention relates to therapeutic compounds and compositions, and methods for their use in the treatment of infection.
  • the invention relates to therapies and methods of treatment for Staphylococcus aureus infection.
  • MRSA methicillin-resistant Staphylococcus aureus
  • MRSA pyruvate kinase MRSA pyruvate kinase
  • MRSA PK MRSA pyruvate kinase
  • Highly connected hub proteins are considered to be associated with cellular essentiality and the removal of a hub protein from a protein interaction network (PIN) is likely to lead to lethality (Park, K. and Kim, D. 2009). Therefore, it is thought that hub protein antibacterial targets may be less likely to develop resistance than conventional targets because their central network positions should make them less tolerant of mutations.
  • MRSA PK was found by Reiner et al. to be one of the most highly connected proteins in the MRSA PIN and it has not yet been exploited as an antibiotic target (Cherkasov, A. et al. 2011).
  • MRSA PK has a number of other attributes that make it an attractive new antibacterial target.
  • Second, a high level of MRSA PK enzymatic activity is observed during the exponential phase of S. aureus growth, which is consistent with its essential role in bacterial replication.
  • MRSA PK is a tetramer that is allosterically activated by AMP and ribose-5-phosphate, which promote the formation of the active R state from the inactive T state by inducing a symmetrical 6° rocking motion of the rigid A and C domain cores of the monomeric units relative to each other at their contact points in the tetramer (Cherkasov, A. et al. 2011; Axerio-Cilies, P. et al. 2012; and Zoraghi, R. et al. 2011).
  • Bioassay guided fractionation of the crude extract identified the fo ' s-indole alkaloids ds-3,4-dihydrohamacanthin B (1) and bromodeoxytopsentin (2) as potent (IC 50 's 16- 60 nM vs MRSA PK) and selective (166 - 600 fold compared with human isoforms) MRSA PK inhibitors that also showed in vitro inhibition of MRSA strains with MIC's in the range of 6 - 12 ⁇
  • the apo- and cis-3,4-dihydrohamacanthin B (2)-bound MRSA PK structures were solved by x- ray diffraction analysis in order to identify the ligand-binding site, characterize the mechanism of action, and provide information for rational design of new inhibitors (Park, K. and Kim, D. 2009).
  • the structure with bound 2 showed a small but significant conformational change in the relative orientation of the monomers in the tetrameric structure compared with the apo protein.
  • This invention is in part based on the discovery certain bis-indole alkaloids as described herein have enhanced efficacy in the treatment of infection.
  • the treatment of Staphylococcus aureus infection or methicillin-resistant Staphylococcus aureus (MRSA) infection may be selected from one or more of Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species.
  • a compound the compound having
  • Ai may be H, Me, Et, Pr, I, F, Br, CI or OH.
  • Ai may be H, Me, I, F, Br, CI or OH.
  • a a may be H, Me, F, Br, CI or OH.
  • A, may be H, F, Br, CI or OH.
  • a t may be H, Me, Et, Pr, I, F, Br or CI.
  • a x may be H, Me, F, Br or CI.
  • A may be H, F, Br or CI.
  • a t may be H, Me, Et, Pr, I, F, Br, CI or OH.
  • A4 may be H, Me, I, F, Br, CI or OH.
  • A4 may be H, Me, F, Br, CI or OH.
  • A4 may be H, F, Br, CI or OH.
  • A4 may be H, Me, Et, Pr, I, F, Br or CI.
  • A4 may be H, Me, F, Br or CI.
  • A, may be H, F, Br or CI.
  • Dj may be H, Me, Et, Pr, I, F, Br, CI or OH.
  • D 1 may be H, Me, I, F, Br, CI or OH.
  • Dj may be H, Me, F, Br, CI or OH.
  • D t may be H, F, Br, CI or OH.
  • Di may be H, Me, Et, Pr, I, F, Br or CI.
  • ⁇ ⁇ may be H, Me, F, Br or CI.
  • D x may be H, F, Br or CI.
  • D 4 may be H, Me, Et, Pr, I, F, Br, CI or OH.
  • D 4 may be H, Me, I, F, Br, CI or OH.
  • D 4 may be H, Me, F, Br, CI or OH.
  • D 4 may be H, F, Br, CI or OH.
  • D 4 may be H, Me, Et, Pr, I, F, Br or CI.
  • D 4 may be H, Me, F, Br or CI.
  • D 4 may be H, F, Br or CI.
  • Ei may be H, Me, Et, Pr, I, F, Br, CI or OH.
  • E t may be H, Me, I, F, Br, CI or OH.
  • Ei may be H, Me, Et, Pr, I, F, Br or CI.
  • Ex may be H, Me, I, F, Br, CI or OH.
  • E, may be H, F, Br, CI or OH.
  • E x may be H.
  • E 2 may be H, Me, Et, Pr, I, F, Br, CI, or OH.
  • E 2 may be H, Me, I, F, Br, CI or OH.
  • E 2 may be H, Me, Et, Pr, I, F, Br or Cl.
  • E 2 may be H, Me, I, F, Br, CI or OH.
  • E 2 may be H, F, Br or Cl.
  • E 2 may be H.
  • A may be H, Me, Et, Pr, I, F, Br or Cl;
  • A4 may be H, Me, Et, Pr, I, F, Br or Cl;
  • D x may be H, Me, Et, Pr, I, F, Br or Cl; and
  • D 4 may be H, Me, Et, Pr, I, F, Br or Cl.
  • Ax may be H.
  • A4 may be H.
  • Dj may be H.
  • D 4 may be H.
  • a 2 may be Br or Cl.
  • D 3 may be H, Br or Cl.
  • a 2 may be Br or Cl; D 3 may be Br or Cl; A 3 may be F; and D 2 may be F.
  • a 2 may be Br.
  • D 3 may be H.
  • a 2 may be Cl.
  • D 3 may be Br or Cl.
  • D 3 may be Cl.
  • the subject may have a bacterial infection.
  • the infection may be a Staphylococcus aureus infection.
  • the infection may be a methicillin-resistant Staphylococcus aureus (MRSA) infection.
  • MRSA methicillin-resistant Staphylococcus aureus
  • the infection may be selected from one or more of Enterococcusfaecalis,
  • Staphylococcus aureus Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species.
  • a pharmaceutical composition including a compound as described above in association with
  • a commercial package comprising (a) a compound as described above in association with Formula I or
  • G 2 may be H, Me, I, F, Br or CI
  • L 3 may be H, Me, I, F, Br or CI
  • G 3 may be CI, Br, F or H
  • L 2 may be CI, Br, F or H
  • may be H, I, F, Br, CI, OH, R 1( R 2 -0- or R 3 -C( 0)-
  • R 2 may be 1-6 carbon
  • G 4 may be H, I, F, Br, Cl, OH or may be H, I, F, Br, Cl, OH or 3 ⁇ 4; and L4 may be H, I, F, Br, Cl, OH or 3 ⁇ 4.
  • d may be H, I, F, Br, Cl, OH or 3 ⁇ 4.
  • G 4 may be H, I, F, Br, Cl, OH or may be H, I, F, Br, Cl, OH or 3 ⁇ 4.
  • L 4 may be H, I, F, Br, Cl, OH or 3 ⁇ 4.
  • d may be H, I, F, Br, Cl or OH.
  • G 4 may be H, I, F, Br, Cl or OH.
  • L4 may be H, I, F, Br, Cl or OH.
  • d may be H, F, Br, Cl or OH.
  • G 4 may be H, F, Br, Cl or OH.
  • L 4 may be H, F, Br, Cl or OH.
  • L 4 may be H, F, Br, Cl or OH.
  • d may be H, I, F, Br or Cl.
  • G 4 may be H, I, F, Br or Cl. may be H, I, F, Br or Cl. may be H, I, F, Br or Cl.
  • Gi may be H, F, Br or Cl.
  • G 4 may be H, F, Br or Cl.
  • L t may be H, F, Br or Cl.
  • L 4 may be H, F, Br or Cl.
  • d may be H, Br or Cl.
  • G 4 may be H, Br or Cl.
  • Li may be H, Br or Cl.
  • L 4 may be H, Br or Cl.
  • d may be F, Br or Cl.
  • G 4 may be F, Br or Cl.
  • L* may be F, Br or Cl. may be F, Br or Cl.
  • Gi may be H or Br.
  • G 4 may be H or Br.
  • X 2 is selected from: ; or ; d may be H, I, F, Br, Cl, OH or Ri; G 4 may be H, I, F, Br, Cl OH or R t ; L x may be H, I, F, Br, Cl, OH or R t ; and L 4 may be H, I, F, Br, Cl, OH or 3 ⁇ 4.
  • d may be H, Me, Et, Pr, I, F, Br or Cl.
  • G 4 may be H, Me, Et, Pr, I, F, Br or Cl.
  • L x may be H, Me, Et, Pr, I, F, Br or Cl.
  • L may be H, Me, Et, Pr, I, F, Br or Cl.
  • d may be H, Me, F, Br or Cl.
  • G 4 may be H, Me, F, Br or Cl. may be H, Me, F, Br or Cl. may be H, Me, F, Br or Cl.
  • d may be H, F, Br or Cl.
  • G 4 may be H, F, Br or Cl. may be H, F, Br or Cl.
  • L 4 may be H, F, Br or Cl.
  • d may be H, Br or Cl.
  • G 4 may be H, Br or Cl. may be H, Br or Cl. may be H, Br or Cl.
  • Gi may be Me, F, Br or Cl.
  • G 4 may be Me, F, Br or Cl.
  • Lj may be Me, F, Br or Cl.
  • G 4 may be H or Br. Li may be H or Br. L, may be H or Br. Gi may be Br or Cl. G 4 may be Br or Cl. Li may be Br or Cl. L 4 may be Br or Cl. Gi may be Br. G 4 may be Br. Li may be Br. L 4 may be Br. d may be H. G 4 may be H. Lj . may be H. may be H. d may be Br, Cl or H; G 4 may be Br, Cl or H; Li may be Br, Cl or H; and L, may be Br, Cl or H.
  • G 2 may be F, Br or Cl; and L 3 may be F, Br or Cl Wherein X 2 is selected from: ; or ; G 2 may be H, I, F, Br or CI; and L 3 may be H, I, F, Br or CI.
  • X 2 may be selected from:
  • X 2 may be selected
  • the compound may be selected from one or more of the followin :
  • the compound may be selected from one or more of the following: 7, 8, 9, 10, 11, 86, 80, T4, T5, T6, T7, T8, T9, T10, Pi, P2, P3, P4, P5, P6, P7, P8, P9, PC-03-29-2 and PC-03-45-3-
  • a method of treating an infection comprising administering a compound of Formula II or
  • a pharmaceutical composition comprising a compound of Formula II or
  • the subject may have a bacterial infection.
  • the infection may be a Staphylococcus aureus infection.
  • the infection may be a methicillin-resistant Staphylococcus aureus (MRSA) infection.
  • MRSA methicillin-resistant Staphylococcus aureus
  • the infection may be selected from one or more of Enterococcusfaecalis,
  • Staphylococcus aureus Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species.
  • a further aspect of this invention provides a method of treating or preventing a nosocomial infection, Staphylococcus infection, or methicillin-resistant Staphylococcus aureus (MRSA) infection reducing or preventing the spread of nosocomial infection, Staphylococcus infection, or MRSA infection, reducing Staphylococcus or MRSA load, or treating or preventing a symptom of nosocomial infection, Staphylococcus infection, or MRSA infection, the method comprises: administering, to a subject who has nosocomial infection, Staphylococcus infection, or MRSA infection, or a symptom of nosocomial infection or MRSA infection, or is at risk of nosocomial infection, Staphylococcus infection, or MRSA infection, an effective amount of a compound of Formula I or Formula II, thereby treating or preventing the nosocomial infection, Staphylococcus infection, or MRSA infection, reducing or preventing the spread of nosocomial infection,
  • FIGURE l shows percent inhibition data of topsentin analogues 5, 6, 7, 8, 9, 10 and 11 against MRSA PK and four mammalian orthologues, with *percent inhibition data at 10 ⁇ .
  • FIGURE 2 shows percent inhibition of MRSA PK for compounds T4, T5, T6, T7, T8, T9 and
  • T10 (abbreviated in the figure as 4, 5, 6, 7, 8, 9 and 10), with results shown for 10 and 100 mM.
  • FIGURE 3A shows the percent inhibition by compound PC-03-29-2 plotted against log concentration at 3 minutes to calculate an IC 50 value.
  • FIGURE 3B shows the MIC for compound PC-03-29-2 against S. aureus (ATCC 29213) where percent growth compared to blank (i.e. no compound PC-03-29-2) is plotted against log concentration.
  • FIGURE 4A shows the percent inhibition by compound PC-03-45-3 plotted against log concentration at 3 minutes to calculate an IC 50 value.
  • FIGURE 4B shows the MIC for compound PC-03-45-3 against S. aureus (ATCC 29213) where percent growth compared to blank (i.e. no compound PC-03-45-3) is plotted against log concentration.
  • FIGURE 5A shows the percent inhibition by compound PC-03-87 plotted against log concentration at 3 minutes to calculate an IC 50 value.
  • FIGURE 5B shows the MIC for compound PC-03-87 against S. aureus (ATCC 29213) where percent growth compared to blank (i.e. no compound PC-03-87) is plotted against log concentration.
  • FIGURE 5C shows the MIC for compound PC-03-87 against Vancomycin-resistant
  • VRE Enterococci
  • PC-03-87 is plotted against log concentration.
  • FIGURE 5D shows the MIC for compound PC-03-87 against A. baumannii where percent growth compared to blank (i.e. no compound PC-03-87) is plotted against log concentration.
  • MRSA PK Methicillin-resistant Staphylococcus aureus pyruvate kinase
  • SAR structure-activity relationship
  • AIDS acquired immunodeficiency syndrome
  • PIN protein interaction network
  • AMP adenosine monophosphate
  • Thr threonine
  • Ser serine
  • Ala alanine
  • Leu leucine
  • NADPH nicotinamide adenine dinucleotide phosphate
  • L-LDH L-lactate dehydrogenase
  • HEPES N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid)
  • ADP adenosine diphosphate
  • PEP phosphoenoylpyruvate.
  • compounds of TABLE 1 and as described in the claims may be used for systemic treatment of infection.
  • MRSA Methicillin- resistant Staphylococcus aureus
  • the compounds described herein may be use to treat infections by one or more of Enter ococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species.
  • compounds of TABLE 1 and as described in the claims may be used in the preparation of a medicament or a composition for systemic treatment of an indication described herein.
  • methods of systemically treating any of the indications described herein are also provided.
  • Compounds as described herein may be in the free form or in the form of a salt thereof.
  • compounds as described herein may be in the form of a pharmaceutically acceptable salt, which are known in the art (Berge S. M. et al., J. Pharm. Set (1977) 66(i):i-l9).
  • Pharmaceutically acceptable salt as used herein includes, for example, salts that have the desired pharmacological activity of the parent compound (salts which retain the biological effectiveness and/or properties of the parent compound and which are not biologically and/or otherwise undesirable).
  • Compounds as described herein having one or more functional groups capable of forming a salt may be, for example, formed as a pharmaceutically acceptable salt.
  • Compounds containing one or more basic functional groups may be capable of forming a pharmaceutically acceptable salt with, for example, a pharmaceutically acceptable organic or inorganic acid.
  • Pharmaceutically acceptable salts may be derived from, for example, and without limitation, acetic acid, adipic acid, alginic acid, aspartic acid, ascorbic acid, benzoic acid, benzenesulfonic acid, butyric acid, cinnamic acid, citric acid, camphoric acid, camphorsulfonic acid, cyclopentanepropionic acid, diethylacetic acid, digluconic acid, dodecylsulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, glucoheptanoic acid, gluconic acid, glycerophosphoric acid, glycolic acid, hemisulfonic acid, heptanoic acid, hexanoic acid, hydrochloric acid, hydrobromic acid, hydriodic
  • Compounds containing one or more acidic functional groups may be capable of forming pharmaceutically acceptable salts with a pharmaceutically acceptable base, for example, and without limitation, inorganic bases based on alkaline metals or alkaline earth metals or organic bases such as primary amine compounds, secondary amine compounds, tertiary amine compounds, quaternary amine compounds, substituted amines, naturally occurring substituted amines, cyclic amines or basic ion-exchange resins.
  • inorganic bases based on alkaline metals or alkaline earth metals or organic bases such as primary amine compounds, secondary amine compounds, tertiary amine compounds, quaternary amine compounds, substituted amines, naturally occurring substituted amines, cyclic amines or basic ion-exchange resins.
  • Pharmaceutically acceptable salts may be derived from, for example, and without limitation, a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation such as ammonium, sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese or aluminum, ammonia, benzathine, meglumine, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, glucamine, methylglucamine, theobromine, purines, piperazine, piperidine, procaine, N-ethylpiperidine, theo
  • compounds as described herein may contain both acidic and basic groups and may be in the form of inner salts or zwitterions, for example, and without limitation, betaines.
  • Salts as described herein may be prepared by conventional processes known to a person skilled in the art, for example, and without limitation, by reacting the free form with an organic acid or inorganic acid or base, or by anion exchange or cation exchange from other salts. Those skilled in the art will appreciate that preparation of salts may occur in situ during isolation and purification of the compounds or preparation of salts may occur by separately reacting an isolated and purified compound.
  • compounds and all different forms thereof may be in the solvent addition form, for example, solvates.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent in physical association the compound or salt thereof.
  • the solvent may be, for example, and without limitation, a pharmaceutically acceptable solvent.
  • hydrates are formed when the solvent is water or alcoholates are formed when the solvent is an alcohol.
  • compounds and all different forms thereof may include crystalline and amorphous forms, for example, polymorphs, pseudopolymorphs, conformational polymorphs, amorphous forms, or a combination thereof.
  • Polymorphs include different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and/or solubility. Those skilled in the art will appreciate that various factors including recrystallization solvent, rate of crystallization and storage temperature may cause a single crystal form to dominate.
  • compounds and all different forms thereof include isomers such as geometrical isomers, optical isomers based on asymmetric carbon, stereoisomers, tautomers, individual enantiomers, individual diastereomers, racemates, diastereomeric mixtures and combinations thereof, and are not limited by the description of the formula illustrated for the sake of convenience.
  • compounds may include analogs, isomers, stereoisomers, or related derivatives.
  • Compounds of the present invention may include compounds related to the compounds of TABLE 1 by substitution or replacement of certain substituents with closely related substituents, for instance replacement of a halogen substituent with a related halogen (i.e. bromine instead of chlorine, etc.) or replacement of an alkyl chain with a related alkyl chain of a different length, and the like.
  • compounds may include compounds within a generic or Markush structure, as determined from structure-activity relationships identified from the data presented in TABLE l. In this way, many different combinations of ring structures may be expected to also be efficacious. The determination of such structure- activity relationships for the development of generic Markush structures is within the skill of one in the art.
  • compositions as described herein may comprise a salt of such a compound, preferably a pharmaceutically or physiologically acceptable salt.
  • Pharmaceutical preparations will typically comprise one or more carriers, excipients or diluents acceptable for the mode of administration of the preparation, be it by injection, inhalation, topical administration, lavage, or other modes suitable for the selected treatment. Suitable carriers, excipients or diluents (used interchangeably herein) are those known in the art for use in such modes of administration.
  • Suitable pharmaceutical compositions may be formulated by means known in the art and their mode of administration and dose determined by the skilled practitioner.
  • a compound may be dissolved in sterile water or saline or a pharmaceutically acceptable vehicle used for administration of non-water soluble compounds such as those used for vitamin K.
  • the compound may be administered in a tablet, capsule or dissolved in liquid form.
  • the tablet or capsule may be enteric coated, or in a formulation for sustained release.
  • Many suitable formulations are known, including, polymeric or protein microparticles encapsulating a compound to be released, ointments, pastes, gels, hydrogels, or solutions which can be used topically or locally to administer a compound.
  • a sustained release patch or implant may be employed to provide release over a prolonged period of time.
  • Many techniques known to one of skill in the art are described in Remington: the Science & Practice of Pharmacy by Alfonso Gennaro, 20 th ed., Lippencott Williams & Wilkins, (2000).
  • Formulations for parenteral administration may, for example, contain excipients, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated naphthalenes.
  • Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds.
  • Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.
  • Compounds or pharmaceutical compositions as described herein or for use as described herein may be administered by means of a medical device or appliance such as an implant, graft, prosthesis, stent, etc.
  • a medical device or appliance such as an implant, graft, prosthesis, stent, etc.
  • implants may be devised which are intended to contain and release such compounds or compositions.
  • An example would be an implant made of a polymeric material adapted to release the compound over a period of time.
  • an “effective amount” of a pharmaceutical composition as described herein includes a therapeutically effective amount or a prophylactically effective amount.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as reduced infection, increased life span or increased life expectancy.
  • a therapeutically effective amount of a compound may vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects.
  • prophylactically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result, such as reduced infection, increased life span, increased life expectancy or prevention of the progression of the infection.
  • a prophylactic dose is used in subjects prior to or at an earlier stage of disease, so that a prophylactically effective amount may be less than a therapeutically effective amount.
  • dosage values may vary with the severity of the condition to be alleviated.
  • specific dosage regimens may be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
  • Dosage ranges set forth herein are exemplary only and do not limit the dosage ranges that may be selected by medical practitioners.
  • the amount of active compound(s) in the composition may vary according to factors such as the disease state, age, sex, and weight of the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It may be advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Toxicity of the compounds as described herein can be determined using standard techniques, for example, by testing in cell cultures or experimental animals and determining the therapeutic index, i.e., the ratio between the LD50 (the dose lethal to 50% of the population) and the LD100 (the dose lethal to 100% of the population). In some circumstances however, such as in severe disease conditions, it may be appropriate to administer substantial excesses of the compositions. Some compounds as described herein may be toxic at some concentrations. Titration studies may be used to determine toxic and non-toxic concentrations.
  • Toxicity may be evaluated by examining a particular compound's or composition's specificity for bacterial pyruvate kinase (PK) as opposed to human PK. Animal studies may be used to provide an indication if the compound has any effects on other tissues or PK enzymes. Systemic therapy that targets the bacterial PK will not likely cause major problems to host tissues since the compounds show bacterial PK specificity.
  • PK bacterial pyruvate kinase
  • a "subject" may be a human, non-human primate, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, etc.
  • the subject may be suspected of having or at risk for having an infection, such as a Staphylococcus aureus infection or Methicillin-resistant Staphylococcus aureus (MRSA) infection.
  • MRSA Methicillin-resistant Staphylococcus aureus
  • the subject may have a vancomycin-resistant Enterococcus or vancomycin-resistant Enterococci (VRE) infection or Acinetobacter baumannii (A. baumannii) infection.
  • the infection may be by any number of bacterial pathogens with a high rate of antibiotic resistance.
  • the Enterococcus faecalis for example, the Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species, the so called ESKAPE pathogens. Diagnostic methods for various infections are known to those of ordinary skill in the art.
  • Scheme 1 General synthetic route to analogues of cis-3,4-dihydrohamacanthin B (71).
  • the synthesis of ( ⁇ )-cis-3,4-dihydrohamacanthin B (71) started with reaction of 6-bromoindole (3) with i-dimethylamino-2-nitroethylene (DMANE) in TFA at rt to give the 6- bromonitroethene 12, which was reduced with LiAlH 4 to give 6-bromotryptamine (Scheme 1).
  • DMANE i-dimethylamino-2-nitroethylene
  • Cyclizing the linker to give pyrazin-2(iH)-one 61 only increases the activity slightly relative to the analogue 51 containing the linear spacer. However, reducing the pyrazin-2(iH)-one ring in 61 to give 71 containing the czs-3,5-diarylpiperazin-2-one heterocycle found in the natural product 2, leads to potent inhibition.
  • the mono-iodo analogue 77 was prepared and it showed significantly reduced activity (7% inhibition) compared with the mono-bromo analogue 72 (38% inhibition), which is opposite from the expected trend for halogen bonding in agreement with the absence of halogen bonding indicated by the x-ray data.
  • the iodine subsitutent may be too large to fit well in the lipophilic binding pocket.
  • Methyl group substituents have similar size and polarity compared with bromine atom substituents on aromatic rings and, therefore, they are often considered to be bioisosteric ⁇ Consistent with this notion, previous work in our laboratory showed that replacing the aromatic bromine substituents in the antimitotic sponge natural product ceratamine A (81) with hydrogen atoms to give 82 dramatically reduced its activity, while replacement of the bromine atoms with methyl groups to give 83 led to significantly increased potency and efficacy (Nodwell, M et al. 2010).
  • the 7,7'-dibromo analogue 78 and the 5,5'-dibromo analogue 79 showed only 22 and 0% inhibition of MRSA PK at 10 ⁇ compared with 71, respectively, confirming that the 6/6' location of the bromine atoms on the 3,4-dihydrohamacanthin scaffold is required for full activity.
  • the indole-3-nitroethylene derivatives were prepared by a previously reported method (Muratore, M.E. et al. 2009) NMR data of 5-Br (Muratore, M.E. et al. 2009), 6-Br (Schumacher, R. W. and Davidson, B. S. 1999), 6-Cl (Hara, T. et al. 2006), and 6-F (Muratore, M.E. et al. 2009) analogues matched that reported in the literature.
  • Deprotection of the oxotryptamine derivatives (28-34) to generate the HBr salts (35-41) was accomplished by dissolving the Cbz-oxytryptamine derivatives (28-34) in hydrobromic acid solution (33% by weight in acetic acid, i3mL/mmol). Evolution of gas was observed and a precipitate began to form within a few minutes. Addition of diethyl ether after 2h initiated further precipitation of the HBr salt, which was filtered, washed with diethyl ether and used without further purification.
  • R 2 F 13
  • R 2 F 56% 6 j s R 3 a H.
  • R F
  • R 3 H
  • R 2 CI 14 R, * R 3 » H
  • the proposed pseudosymmetrical synthetic targets (6-9) featuring a C- 6 halogen substituent on each indole ring were prepared via a one-pot selenium dioxide- mediated oxidation (Marchand, N. J. et al. 1996; and Young, R. M. and Davies-Coleman, M. T. 2011) of appropriate 3-acetylindoles to the corresponding indolyl-3-glyoxals.
  • two molecules of indolyl-3-glyoxal then undergo dehydrative cyclocondensation in EtOH at room temperature (Khalili, B. et al. 2009) to yield the desired bisindole imidazoles (33-37, Scheme 2).
  • a similar approach was used to prepare the nonhalogenated 5 and the C-5 dibromo and C-7 dichloro analogues.
  • organo-selenium byproducts e.g., from Se(II) addition to susceptible olefins (Umbreit, M.A. and Sharpless, K.B.J. 1977).
  • Se(II) addition to susceptible olefins Umbreit, M.A. and Sharpless, K.B.J. 1977.
  • TBHP additional oxidizing agent
  • halogenated analogues (26-31) were successfully oxidized at higher yields over two steps when subjected to higher equivalents of Se0 2 prior to cyclization than in the case of 25. Due to limited starting material availability, reactions of compounds 29 and 30 were conducted on a smaller scale, with disappointingly low yields, but gratifyingly significant proportions of recoverable starting materials that could be recycled. Thermolytic cleavage (Knott, K. E. et al. 2009) of Boc-protected topsentins (32-38) proceeded smoothly to yield the desired fluorescent deoxytopsentin pigments, which were subjected to RP-HPLC purification prior to bioassay.
  • Halogenated deoxytopsentin analogues 6-10 were found to be potent inhibitors of MRSA PK (TABLE 1).
  • High-resolution mass spectrometry was performed on a Waters Synapt G2TM TOF instrument with an ESI source. Flash chromatography was performed using Kieselgel 60TM (230-400 mesh) silica gel. Purity of all tested compounds was >95 , determined by semi-preparative RP-HPLC, with an Onyx MonolithicTM Ci8 column, 100 x 10 mm, on an Agilent 1100 SeriesTM quad pump and an Agilent 1100TM diode array detector.
  • Boc 2 0 (2020 mg, 1.5 equiv) and DMAP (77 mg, 0.1 equiv) were added to a stirring solution of 12 (1000 mg, 6.3 mmol, 1 equiv) in HPLC grade MeCN (15 mL) at o°C under an atmosphere of argon. After 3 h the MeCN was removed in vacuo and the solid recrystallized from MeOH to yield 25 (1565 mg, 6.04 mmol, 96%). The same procedure was applied to varying quantities of 3-acetylindoles 13-18 depending on availability using the same equivalents and solvent ratios as above. Compounds 25 (Carmen de la Fuente, M. and Dominguez, D. 2011) and 29 (Moody, C.J. and Roffey, J.R.A. 2000) have been reported previously.
  • Freshly sublimed Se02 (286 mg, 2.59 mmol, 2.7 equiv) was added to a mixture of 1,4-dioxane (7 mL) and H 2 0 (200 ⁇ ,, n equiv), after which the reaction mixture was heated to 60 °C to allow all the Se0 2 to dissolve. To this was added 25 (250 mg, 0.96 mmol, 1 equiv), and the temperature increased to 75 °C. After 6 h the crude reaction mixture was filtered through Celite, which was washed with CH 2 C1 2 (20 mL).
  • Schemes 4a and 4b Synthetic route for 27 or 28 to 31 or 32 respectively.
  • Oxalyl chloride (420 ml, 4.8 mmol, 1.13 equiv) was added dropwise to a stirred solution of indole (500 mg, 4.26 mmol, 1 equiv) in dry Et 2 0 (10 mL) at o °C under an inert atmosphere of dry argon gas, resulting in an instant colour change from clear to yellow.
  • dry toluene (20 mL) and HPLC grade MeCN (4 mL) were added, followed by CuCN (1144.5 mg, 3 equiv), which was sprinkled in to the solution over 2 min to avoid aggregation.
  • reaction mixture was refluxed at 110 °C and after 2 h the reaction mixture was cooled and concentrated in vacuo to yield a black solid, which was subjected to flash chromatography (100% CH 2 C1 2 ) yielding 27 as a yellow crystalline solid (529 mg, 3.10 mmol, 73%).
  • a crystal of czs-3,4-dihydrohamacanthin B (1) bound to MRSA PK provided the first x-ray crystal structure of MRSA PK and it identified a new allosteric binding site as well as providing information about the important binding interactions.
  • An essential feature of the binding appeared to be an interaction between the bromine substituents at the 6 positions on both of the indole rings and a pair of lipophilic binding pockets.
  • 6-bromo-5-fluoroindole moiety confers significantly better MRSA PK inhibition activity to the cis-3,4-dihydrohamacanthin scaffold than the naturally occurring 6-bromoindole fragments.
  • Reactions were carried out in oven (130 °C) or flame-dried glassware under a positive argon atmosphere unless otherwise stated. Transfer of anhydrous reagents was accomplished with oven-dried syringes or cannulae. Commercially available anhydrous solvents were used without further purification with the exception of tetrahydrofuran (THF), which was distilled before use over sodium metal.
  • THF tetrahydrofuran
  • Proton nuclear magnetic resonance spectra ( ⁇ NMR) were recorded at 300 MHz, 400 MHz, or 600 MHz and coupling constants (J) are reported in Hertz (Hz). Carbon nuclear magnetic resonance spectra ( ⁇ C NMR) were recorded at 100 MHz or 150 MHz.
  • MRSA and human PK isoforms were sourced as His-tagged constructs, via a method described previously (Zoraghi, R. et al. 2011 a).
  • PK inhibitory activity was determined by measuring UV absorbance changes of NADPH at 340 nm in a continuous assay coupled to rabbit muscle lactate dehydrogenase (L-LDH). Absorbance was measured using a Benchmark PlusTM microplate spectrophotometer (Bio-RadTM).
  • the reaction contained 60 niM Na + -HEPES, pH 7.5, 5% glycerol, 67 mM KC1, 6.7 mM MgCl 2 , 0.24 mM NADH, 5.5 units L-LDH, 2 mM ADP, and 10 mM PEP.
  • Assayed compounds were dissolved in DMSO with final concentrations of DMSO never exceeding 1% of the assay volume.
  • IC50 values were calculated by curve fitting on a four parameter dose-response model with variable slope using Graphpad Prism 5.0TM (La Jolla, CA). All values determined represent three measurements, each in triplicate.
  • Enzymatic activity was determined using a continuous assay coupled to lactate dehydrogenase (LDH), in which the change in absorbance at 340 nm due to the oxidation of NADH was measured with a Benchmark PlusTM microplate spectrophotometer (Bio-RadTM).
  • LDH lactate dehydrogenase
  • the reaction mixture contained 60 mM Na+- HEPES (pH 7.5), 5% glycerol, 67 mM KC1, 6.7 mM MgCl 2 , 0.24 mM NADH, 15 nM PK, 2 mM ADP, and 10 mM P-enolpyruvate (i.e., close to the Michaelis-Menten constant [Km] of MRSA PK so that the IC 50 values should approximate the inhibition constant [Ki]) in a total volume of 200 ⁇ L ⁇ Reactions were initiated by the addition of the appropriate 5.5 units L-lactate dehydrogenase from rabbit muscle (Sigma AldrichTM) enzyme to the mixture.
  • PK activity proportional to the rate of the change at 340 nm was expressed as specific activity ⁇ mol/rnin/mg), which is defined as the amount of PK that catalyzes the formation of 1 ⁇ of either product per minute.
  • Compounds were dissolved in DMSO, with the final concentration of solvent never exceeding 1% of the assay volume.
  • IC 50 values were calculated by curve fitting on a four-parameter dose-response model with a variable slope using GraphPad Prism 5.0TM (GraphPad SoftwareTM, Inc., La Jolla, CA). In all studies less than 10% of the Penolpyruvate was exhausted during the reaction. Reactions were performed at 30 °C for up to 5 min. All values determined are mean of two measurements, each in triplicate.
  • PK inhibitor candidates were determined at 2 single concentrations of 64 and 128 ⁇ /ml by using the 96-well microtiter standard method, as described by the CLSI [formerly National Committee for Clinical Laboratory Standards (NCCLS)] in Watts, J. L.; Shryock, T. R.; Apley, M.; Bade, D. J.; Brown, S. D.; Gray, J. T.; Heine, H.; Hunter, R. P.; Mevius, D. J.; Papich, M. G.; Silley, P.; Zurenk, G. E. Clin. Lab. Stand. Inst. 2008, 28 (M31-A3)., with S. aureus ATCC 29213.
  • CLSI National Committee for Clinical Laboratory Standards
  • bacteria from a single colony were grown overnight in cation adjusted Mueller Hinton Broth (MHCAB) (SigmaTM), harvested by centrifugation, and then washed twice with sterile distilled water.
  • MHCAB Mueller Hinton Broth
  • Each stock solution of compounds in DMSO was diluted with MHCAB broth to prepare dilutions of 128 and 64 ⁇ g/ml.
  • MRSA PK The inhibition of MRSA PK was apparently unaffected by bromination at C-5 (i.e., 10), while chlorination at C-7 (i.e., 11) resulted in a dramatic loss of activity.
  • Compounds 6, 8, and 9 were further found to completely inhibit MRSA enzymatic activity at a concentration of 5 ⁇ , while simultaneously exhibiting zero inhibition of human PK orthologues Ml and M2 and less than 40% inhibition of human PK orthologues R and L at the same concentration, a result potentially attributed to sequence divergence in the binding site.
  • a slight drop in inhibitory activity was observed with the C-5-halogenated analogue 10, while also displaying a similar pattern of human PK inhibition (see FIGURE 1).
  • TABLE 1 shows the compounds tested by the associated identifier, by structure and the activity. All chiral compounds were tested as racemates.
  • PC-03-29-2 has an IC50 of 63.054 ⁇ as calculated after 3 minute reaction time.
  • the MIC value for PC-03-29-2 tested on S. aureus (ATCC 29213) was 32 ⁇ g/ml.
  • EXAMPLE 5 IC 5 o and MIC Values for PC-03-45-3 Analogue
  • PC-03-45-3 has an IC50 of 0.04643 ⁇ as calculated after 3 minute reaction time.
  • the MIC value for PC-03-45-3 tested on S. aureus (ATCC 29213) was 8 / ⁇ .
  • PC-03-87 has an IC50 of 0.04163 ⁇ as calculated after 3 minute reaction time.
  • the MIC value for PC-03-87 tested on S. aureus was 8 ⁇ g/ml.
  • MIC values for PC-03-87 were determined for Vancomycin-resistant Enterococcus (VRE) and A. baumannii as 8 ⁇ / ⁇ and 16 ⁇ g/ml, respectively (see FIGURES 5C and 5D).
  • Lu Y.; Liu, Y.; Xu, Z.; Li, H.; Liu, H.; Zhu, W. Expert Opin. Drug Discov. 2012, 7, 375-383.

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Abstract

La présente invention concerne des alcaloïdes bis-indoliques de formules I et II et des compositions pharmaceutiques de ceux-ci utiles dans le traitement d'infections bactériennes telles que Staphylococcus aureus (SARM). Dans lesdites formules, X1 désigne: X2 désigne:
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CN107810961A (zh) * 2016-09-12 2018-03-20 南开大学 Topsentin类生物碱在抗植物病毒和病菌中的应用
EP3301096A1 (fr) * 2016-09-30 2018-04-04 Heinrich-Heine-Universität Düsseldorf Derives de bis-indoles pour le traitement des infections bacteriennes
WO2019099977A3 (fr) * 2017-11-20 2019-09-12 Ariagen, Inc. Composés d'indole et leur utilisation
US11390621B2 (en) 2019-04-15 2022-07-19 Ariagen, Inc. Chiral indole compounds and their use
US11547698B2 (en) 2016-12-26 2023-01-10 Ariagen, Inc. Aryl hydrocarbon receptor modulators
WO2023068703A1 (fr) * 2021-10-20 2023-04-27 동국대학교 와이즈캠퍼스 산학협력단 Procédé de production de durumamide

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107810961A (zh) * 2016-09-12 2018-03-20 南开大学 Topsentin类生物碱在抗植物病毒和病菌中的应用
CN107810961B (zh) * 2016-09-12 2021-04-02 南开大学 Topsentin类生物碱在抗植物病毒和病菌中的应用
EP3301096A1 (fr) * 2016-09-30 2018-04-04 Heinrich-Heine-Universität Düsseldorf Derives de bis-indoles pour le traitement des infections bacteriennes
WO2018060367A1 (fr) * 2016-09-30 2018-04-05 Heinrich-Heine Universität Düsseldorf Composés utilisés pour le traitement d'infections bactériennes
US11547698B2 (en) 2016-12-26 2023-01-10 Ariagen, Inc. Aryl hydrocarbon receptor modulators
WO2019099977A3 (fr) * 2017-11-20 2019-09-12 Ariagen, Inc. Composés d'indole et leur utilisation
US11427576B2 (en) 2017-11-20 2022-08-30 Ariagen, Inc. Indole compounds and their use
US11459322B2 (en) 2017-11-20 2022-10-04 Ariagen, Inc. Indole compounds and their use
US11891386B2 (en) 2017-11-20 2024-02-06 Ariagen, Inc. Indole compounds and their use
US11390621B2 (en) 2019-04-15 2022-07-19 Ariagen, Inc. Chiral indole compounds and their use
WO2023068703A1 (fr) * 2021-10-20 2023-04-27 동국대학교 와이즈캠퍼스 산학협력단 Procédé de production de durumamide

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