WO2018172733A1 - Combinaisons de polymyxines - Google Patents

Combinaisons de polymyxines Download PDF

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Publication number
WO2018172733A1
WO2018172733A1 PCT/GB2018/050577 GB2018050577W WO2018172733A1 WO 2018172733 A1 WO2018172733 A1 WO 2018172733A1 GB 2018050577 W GB2018050577 W GB 2018050577W WO 2018172733 A1 WO2018172733 A1 WO 2018172733A1
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WIPO (PCT)
Prior art keywords
dab
combination
thr
pharmaceutically acceptable
mycobacterium
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PCT/GB2018/050577
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English (en)
Inventor
Professor Anthony COATES
Yanmin Hu
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Helperby Therapeutics Limited
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Publication of WO2018172733A1 publication Critical patent/WO2018172733A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/60—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation occurring through the 4-amino group of 2,4-diamino-butanoic acid
    • C07K7/62—Polymyxins; Related peptides

Definitions

  • the present invention relates to the use of at least one antibiotic resistance breaker selected from zidovudine, mefloquine, suloctidil, phenoxybenzamine or a pharmaceutically acceptable derivative thereof in combination with a polymyxin derivative of formula (I) as defined herein or pharmaceutically acceptable salts thereof for treating bacterial infections.
  • at least one antibiotic resistance breaker selected from zidovudine, mefloquine, suloctidil, phenoxybenzamine or a pharmaceutically acceptable derivative thereof in combination with a polymyxin derivative of formula (I) as defined herein or pharmaceutically acceptable salts thereof for treating bacterial infections.
  • Polymyxins are a group of closely related antibiotic substances with a general structure consisting of a cyclic peptide and a hydrophobic tail. They are produced by non- ribosomal peptide synthetase systems in Gram-positive bacteria such as Paenibacillus polymyxa, and are selectively toxic for Gram-negative bacteria due to their specificity for the lipopolysaccharide molecule that exists within many Gram-negative outer membranes. Polymyxins B and E are used in the treatment of Gram-negative bacterial infections.
  • ⁇ - ⁇ 3 ⁇ 3 ⁇ / ⁇ - ⁇ 3 ⁇ 3 ⁇ 33 ⁇ inhibitor combinations include Tazocin® (piperacillin/tazobactam), Avycaz® (ceftazidime/avibactam) and Carbassemble® (meropenem/vaborbactam).
  • WO2012032360 discloses a combination comprising phenoxybenzamine or a pharmaceutically acceptable derivative thereof and a polymyxin selected from polymyxin E and polymyxin B or a pharmaceutically acceptable derivative thereof, and its use in treating a microbial infection.
  • WO2014147405 then discloses the use of colistin (polymyxin E) in combination with zidovudine for treating a microbial infection.
  • WO2016097754 discloses a combination comprising suloctidil or a pharmaceutically acceptable derivative or prodrug thereof, and a polymyxin selected from polymyxin E and polymyxin B or a pharmaceutically acceptable derivative thereof, and its use in treating a microbial infection.
  • a polymyxin derivative of formula (I) defined herein or a pharmaceutically acceptable salt thereof is combined with at least one antibiotic resistance breaker selected from zidovudine, phenoxybenzamine, mefloquine, suloctidil or a pharmaceutically acceptable derivative thereof.
  • the inventors surprising found that these combinations exhibit synergistic antibacterial activity against bacteria, particularly against Gram-negative bacteria.
  • the combinations were unexpectedly found to have a greater biological activity than the expected additive effect of each agent at the stated dosage level.
  • the surprising biological activity of the combinations of the present invention offers the opportunity to shorten chemotherapy regimens and may result in a reduction in the emergence of microbial resistance associated with the use of such combinations.
  • the combinations of the present invention have also been demonstrated to be particularly effective against drug- resistant bacteria, particularly drug-resistant Gram-negative bacteria. This opens the way for the combinations to be administered both to drug-resistant strains and in said strains before drug-resistance is built up, i.e. as a first line treatment.
  • Synergy in the context of antimicrobials drugs is measured in a number of ways that conform to the generally accepted opinion that "synergy” is an effect greater than additive.
  • One of the ways to assess whether synergy has been observed is to use the "chequerboard” technique. This is a well-accepted method that leads to the generation of a value called the fractional inhibitory concentration index (FICI).
  • FICI fractional inhibitory concentration index
  • the FICI value is a ratio of the sum of the MIC (Minimum Inhibitory Concentration) level of each individual component alone and in the mixture.
  • the combination is considered synergistic when the ⁇ FIC is ⁇ 0.5, indifferent when the ⁇ FIC is >0.5 to ⁇ 2, and antagonistic when the ⁇ FIC is ⁇ 2.
  • Another accepted test for ascertaining the presence or absence of synergy is to use time-kill methods where the dynamic effect of a drug combination is compared to each drug alone when assessing the effect on bacterial log or stationary-growth over time. Again, the possible results are synergy, indifference, or antagonism.
  • the present invention provides a combination comprising a polymyxin derivative of formula (I):
  • R2 is Thr
  • R3 is DThr
  • R4 is Dab
  • R5 is Dab
  • R6 is DPhe
  • R7 is Leu
  • R8 is Abu
  • R9 is Dab
  • R10 is Thr
  • R(FA) is octanoyl
  • R1 is absent
  • R2 is Thr
  • R3 is DSer
  • R4 is Dab
  • R5 is Dab
  • R6 is DPhe
  • R7 is Leu
  • R8 is Dab
  • R9 is Dab
  • R10 is Thr
  • R(FA) is octanoyl
  • antibiotic resistance breaker selected from the group consisting of zidovudine, suloctidil, mefloquine, phenoxybenzamine or a pharmaceutically acceptable derivative thereof.
  • the present invention provides the use of a polymyxin derivative of formula (I) as defined hereinabove or a pharmaceutically acceptable salt thereof, and at least one antibiotic resistance breaker selected from the group consisting of zidovudine, suloctidil, mefloquine, phenoxybenzamine or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for treating a bacterial infection.
  • the present invention provides the combination of a polymyxin derivative of formula (I) as defined hereinabove or a pharmaceutically acceptable salt thereof, and at least one antibiotic resistance breaker selected from the group consisting of zidovudine, suloctidil, mefloquine, phenoxybenzamine or a pharmaceutically acceptable derivative thereof, for use in the treatment of a bacterial infection.
  • the invention provides a method of treating a bacterial infection which comprises administering the combination of a polymyxin derivative of formula (I) as defined hereinabove or a pharmaceutically acceptable salt thereof, and at least one antibiotic resistance breaker selected from the group consisting of zidovudine, suloctidil, mefloquine, phenoxybenzamine or a pharmaceutically acceptable derivative thereof, to a patient in need thereof.
  • a pharmaceutical composition comprising a polymyxin derivative of formula (I) as defined hereinabove or a pharmaceutically acceptable salt thereof, and at least one antibiotic resistance breaker selected from the group consisting of zidovudine, suloctidil, mefloquine, phenoxybenzamine or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition is for use in treating a bacterial infection.
  • the invention relates to a product comprising a polymyxin derivative of formula (I) or a pharmaceutically acceptable salt thereof as defined hereinabove, and at least one antibiotic resistance breaker selected from the group consisting of zidovudine, suloctidil, mefloquine, phenoxybenzamine or a pharmaceutically acceptable derivative thereof, as a combined preparation for simultaneous, separate or sequential use in treating a bacterial infection.
  • cy or cyclo refers to the cyclic part of the peptide, enclosed within brackets; Dab or Dbu refers to ⁇ , ⁇ -diamino-n-butyryl (i.e. 2,4-diaminobutyryl); Abu refers to 2- aminobutyryl; Thr refers to L-threonine; DThr refers to D-threonine; DPhe refers to D- phenylamine; Leu refers to L-leucine; DSer refers to D-serine and OA refers to octanoyl.
  • physiological pH refers to a pH value of more than 7.0 and below 7.6, such as a pH value in the range of from 7.1 to 7.5, for example in the range of from 7.2 to 7.4.
  • antibiotic resistance breaker refers to non-antibiotic compounds that, when combined with existing antibiotics, act to block resistance or enhance antibacterial activity. These compounds are also known in the art as “antibiotic adjuvants”, “resistance breakers” and “antibiotic potentiators”.
  • the antibiotic resistance breakers in the present invention are selected from the group consisting of zidovudine, suloctidil, mefloquine, phenoxybenzamine or pharmaceutically acceptable derivatives thereof. All of these compounds are known non-antibiotic drugs.
  • the term "in combination with” covers both separate and sequential administration of the polymyxin derivative and antibiotic resistance breaker (ARB).
  • either the polymyxin derivative or ARB may be administered first.
  • the polymyxin derivative or ARB may be administered either in the same or a different pharmaceutical composition.
  • Adjunctive therapy i.e. where one agent is used as a primary treatment and the other agent is used to assist that primary treatment, is also an embodiment of the present invention.
  • the combinations of the present invention may be used to treat bacterial infections.
  • they may be used to kill multiplying, non-multiplying and/or clinically latent bacteria associated with bacterial infections, preferably multiplying or non-multiplying bacteria, more preferably multiplying bacteria, e.g. multiplying bacteria associated with Gram-negative bacterial infections.
  • references herein to the treatment of a bacterial infection include killing multiplying, non- multiplying and/or clinically latent bacteria associated with such infections.
  • kill means a loss of viability as assessed by a lack of metabolic activity.
  • clinical latent bacteria means a bacterium that is metabolically active but has a growth rate that is below the threshold of infectious disease expression.
  • the threshold of infectious disease expression refers to the growth rate threshold below which symptoms of infectious disease in a host are absent.
  • clinically latent bacteria can be determined by several methods known to those skilled in the art; for example, by measuring mRNA levels in the bacterium or by determining their rate of uridine uptake.
  • clinically latent bacteria when compared to bacteria under logarithmic growth conditions (in vitro or in vivo), possess reduced but still significant levels of:
  • mRNA e.g. from 0.0001 to 50%, such as from 1 to 30, 5 to 25 or 10 to 20%, of the level of mRNA
  • uridine e.g. [ 3 H]uridine
  • uptake e.g. from 0.0005 to 50%, such as from 1 to 40, 15 to 35 or 20 to 30% of the level of [ 3 H]uridine uptake.
  • Clinically latent bacteria typically possess a number of identifiable characteristics. For example, they may be viable but non-culturable; i.e. they cannot typically be detected by standard culture techniques, but are detectable and quantifiable by techniques such as broth dilution counting, microscopy, or molecular techniques such as polymerase chain reaction.
  • clinically latent bacteria are typically phenotypically tolerant, and as such are sensitive (in log phase) to the biostatic effects of conventional antimicrobial agents (i.e.
  • bacteria for which the minimum inhibitory concentration (MIC) of a conventional antimicrobial is substantially unchanged); but possess drastically decreased susceptibility to drug-induced killing e.g. bacteria for which, with any given conventional antimicrobial agent, the ratio of minimum microbiocidal concentration (e.g. minimum bactericidal concentration, MBC) to MIC is 10 or more).
  • bacteria and derivatives thereof, such as “bacterial infection” includes, but is not limited to, references to organisms (or infections due to organisms) of the following classes and specific types:
  • Gram-positive cocci such as Staphylococci (e.g. Staph, aureus, Staph, epidermidis, Staph, saprophyticus, Staph, auricularis, Staph, capitis capitis, Staph, c. ureolyticus, Staph, caprae, Staph, cohnii cohnii, Staph, c. urealyticus, Staph, equorum, Staph, gallinarum, Staph, haemolyticus, Staph, hominis hominis, Staph, h. novobiosepticius, Staph, hyicus, Staph.
  • Staphylococci e.g. Staph, aureus, Staph, epidermidis, Staph, saprophyticus, Staph, auricularis, Staph, capitis capitis, Staph, c. ureolyticus
  • Streptococci e.g.beta-haemolytic, pyogenic streptococci (such as Strept. agalactiae, Strept. canis, Strept. dysgalactiae dysgalactiae, Strept. dysgalactiae equisimilis, Strept. equi equi, Strept. equi zooepidemicus, Strept. iniae, Strept. porcinus and Strept. pyogenes),
  • microaerophilic, pyogenic streptococci Streptococcus "milleri”, such as Strept. anginosus, Strept. constellatus constellatus, Strept. constellatus pharyngidis and Strept. intermedius
  • oral streptococci of the "mitis” alpha-haemolytic - Streptococcus “viridans”, such as Strept. mitis, Strept. oralis, Strept. sanguinis, Strept. cristatus, Strept. gordonii and Strept. parasanguinis
  • "salivarius” non-haemolytic, such as Strept. salivarius and Strept.
  • mutans teeth-surface streptococci, such as Strept. criceti, Strept. mutans, Strept. ratti and Strept. sobrinus
  • Strept. acidominimus Strept. bovis, Strept. faecalis, Strept. equinus, Strept. pneumoniae and Strept. suis, or Streptococci alternatively classified as Group A, B, C, D, E, G, L, P, U or V Streptococcus
  • Streptococci alternatively classified as Group A, B, C, D, E, G, L, P, U or V Streptococcus
  • Gram-negative cocci such as Neisseria gonorrhoeae, Neisseria meningitidis, Neisseria cinerea, Neisseria elongata, Neisseria flavescens, Neisseria lactamica, Neisseria mucosa, Neisseria sicca, Neisseria subflava and Neisseria weaveri;
  • Bacillaceae such as Bacillus anthracis, Bacillus subtilis, Bacillus thuringiensis, Bacillus stearothermophilus and Bacillus cereus;
  • Enterobacteriaceae such as Escherichia coli
  • Enterobacter e.g. Enterobacter aerogenes, Enterobacter agglomerans and Enterobacter cloacae
  • Citrobacter such as Citrob. freundii and Citrob. divernis
  • Hafnia e.g. Hafnia alvei
  • Erwinia e.g. Erwinia persicinus
  • Morganella morganii Salmonella (Salmonella enterica and Salmonella typhi), Shigella (e.g. Shigella dysenteriae, Shigella flexneri, Shigella boydii and Shigella sonnei), Klebsiella (e.g. Klebs. pneumoniae, Klebs. oxytoca, Klebs.
  • Proteus e.g. Pr. mirabilis, Pr. rettgeri and Pr. vulgaris
  • Providencia e.g. Providencia alcalifaciens, Provide
  • Enterococci e.g. Enterococcus avium, Enterococcus casseliflavus, Enterococcus cecorum, Enterococcus dispar, Enterococcus durans, Enterococcus faecalis, Enterococcus faecium, Enterococcus flavescens, Enterococcus gallinarum, Enterococcus hirae, Enterococcus malodoratus, Enterococcus mundtii, Enterococcus pseudoavium, Enterococcus raffinosus and Enterococcus solitarius);
  • Enterococci e.g. Enterococcus avium, Enterococcus casseliflavus, Enterococcus cecorum, Enterococcus dispar, Enterococcus durans, Enterococcus faecalis, Enterococcus faecium, Enterococcus flavescens, Enter
  • Helicobacter e.g. Helicobacter pylori, Helicobacter cinaedi and Helicobacter fennelliae
  • Acinetobacter e.g. A. baumanii, A. calcoaceticus, A. haemolyticus, A. johnsonii, A. junii, A. Iwoffi and A. radioresistens
  • Pseudomonas e.g. Ps. aeruginosa, Ps. maltophilia (Stenotrophomonas maltophilia), Ps. alcaligenes, Ps. chlororaphis, Ps. fluorescens, Ps. luteola. Ps. mendocina, Ps. monteilii, Ps. oryzihabitans, Ps. pertocinogena, Ps. pseudalcaligenes, Ps. putida and Ps. stutzeri);
  • Peptococcus e.g. Peptococcus niger
  • Peptostreptococcus Peptostreptococcus
  • Clostridium e.g. C. perfringens, C. difficile, C. botulinum, C. tetani, C. absonum, C. argentinense, C. baratii, C. bifermentans, C. beijerinckii, C. butyricum, C. cadaveris, C. carnis, C. celatum, C. clostridioforme, C. cochlearium, C. cocleatum, C. fallax, C. ghonii, C. glycolicum, C. haemolyticum, C. hastiforme, C. histolyticum, C. indolis, C. innocuum, C. irregulare, C.
  • leptum leptum, C. limosum, C. malenominatum, C. novyi, C. oroticum, C. paraputrificum, C. piliforme, C. putrefasciens, C. ramosum, C. septicum, C. sordelii, C. sphenoides, C. sporogenes, C. subterminale, C. symbiosum and C. tertium);
  • Mycoplasma e.g. M. pneumoniae, M. hominis, M. genitalium and M. urealyticum
  • Mycobacteria e.g. Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium fortuitum, Mycobacterium marinum, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium abscessus, Mycobacterium leprae, Mycobacterium smegmitis,
  • Mycobacterium africanum Mycobacterium alvei, Mycobacterium asiaticum, Mycobacterium aurum, Mycobacterium bohemicum, Mycobacterium bovis, Mycobacterium branderi,
  • Mycobacterium brumae Mycobacterium celatum, Mycobacterium chubense, Mycobacterium confluentis, Mycobacterium conspicuum, Mycobacterium cookii, Mycobacterium flavescens, Mycobacterium gadium, Mycobacterium gastri, Mycobacterium genavense, Mycobacterium gordonae, Mycobacterium goodii, Mycobacterium haemophilum, Mycobacterium hassicum, Mycobacterium intracellular, Mycobacterium interjectum, Mycobacterium heidelberense, Mycobacterium lentiflavum, Mycobacterium malmoense, Mycobacterium microgenicum, Mycobacterium microti, Mycobacterium mucogenicum, Mycobacterium neoaurum, Mycobacterium nonchromogenicum, Mycobacterium peregrinum, Mycobacterium phlei, Mycobacterium scrofulaceum, Mycobacterium shimoidei, My
  • Haemophilus influenzae Haemophilus ducreyi, Haemophilus aegyptius, Haemophilus parainfluenzae, Haemophilus haemolyticus and Haemophilus parahaemolyticus) ;
  • Actinobacillus e.g. Actinobacillus actinomycetemcomitans, Actinobacillus equuli, Actinobacillus hominis, Actinobacillus lignieresii, Actinobacillus suis and Actinobacillus ureae
  • Actinobacillus e.g. Actinobacillus actinomycetemcomitans, Actinobacillus equuli, Actinobacillus hominis, Actinobacillus lignieresii, Actinobacillus suis and Actinobacillus ureae
  • Actinomyces e.g. Actinomyces israelii
  • Brucella e.g. Brucella abortus, Brucella canis, Brucella melintensis and Brucella suis
  • Brucella abortus e.g. Brucella abortus, Brucella canis, Brucella melintensis and Brucella suis
  • Campylobacter e.g. Campylobacter jejuni, Campylobacter coli, Campylobacter lari and Campylobacter fetus
  • Listeria monocytogenes Listeria monocytogenes
  • Vibrio e.g. Vibrio cholerae and Vibrio parahaemolyticus, Vibrio alginolyticus, Vibrio carchariae, Vibrio fluvialis, Vibrio furnissii, Vibrio hollisae, Vibrio metschnikovii, Vibrio mimicus and Vibrio vulnificus
  • Vibrio e.g. Vibrio cholerae and Vibrio parahaemolyticus, Vibrio alginolyticus, Vibrio carchariae, Vibrio fluvialis, Vibrio furnissii, Vibrio hollisae, Vibrio metschnikovii, Vibrio mimicus and Vibrio vulnificus
  • Corynebacteriaceae e.g. Corynebacterium diphtheriae, Corynebacterium jeikeum and Corynebacterium urealyticum
  • Corynebacteriaceae e.g. Corynebacterium diphtheriae, Corynebacterium jeikeum and Corynebacterium urealyticum
  • Spirochaetaceae such as Borrelia (e.g. Borrelia recurrentis, Borrelia burgdorferi, Borrelia afzelii, Borrelia andersonii, Borrelia bissettii, Borrelia garinii, Borrelia japonica, Borrelia lusitaniae, Borrelia tanukii, Borrelia turdi, Borrelia valaisiana, Borrelia caucasica, Borrelia crocidurae, Borrelia duttoni, Borrelia graingeri, Borrelia hermsii, Borrelia hispanica, Borrelia latyschewii, Borrelia mazzottii, Borrelia parkeri, Borrelia persica, Borrelia turicatae and Borrelia venezuelensis) and Treponema (Treponema pallidum ssp.
  • Borrelia e.g. Borrelia recurrentis, Bor
  • Pasteurella e.g. Pasteurella aerogenes, Pasteurella bettyae, Pasteurella canis, Pasteurella dagmatis, Pasteurella gallinarum, Pasteurella haemolytica, Pasteurella multocida multocida, Pasteurella multocida gallicida, Pasteurella multocida septica, Pasteurella pneumotropica and Pasteurella stomatis
  • Bordetella e.g. Bordetella bronchiseptica, Bordetella hinzii, Bordetella holmseii, Bordetella parapertussis, Bordetella pertussis and Bordetella trematum
  • Bordetella e.g. Bordetella bronchiseptica, Bordetella hinzii, Bordetella holmseii, Bordetella parapertussis, Bordetella pertussis and Bordetella trematum
  • Nocardiaceae such as Nocardia (e.g. Nocardia asteroides and Nocardia brasiliensis);
  • Rickettsia e.g. Ricksettsii or Coxiella burnetii
  • Legionella e.g. Legionalla anisa, Legionalla birminghamensis, Legionalla bozemanii, Legionalla nucleophili, Legionalla birminghamensis, Legionalla bozemanii, Legionalla nucleophili, Legionalla birminghamensis, Legionalla bozemanii, Legionalla nucleophili, Legionalla birminghamensis, Legionalla bozemanii, Legionalla nucleaii, Legionalla dumoffii, Legionalla feeleii, Legionalla gormanii, Legionalla hackeliae, Legionalla israelensis, Legionalla jordanis, Legionalla lansingensis, Legionalla longbeachae, Legionalla maceachernii, Legionalla micdadei, Legionalla oakridgensis, Legionalla pneumophila, Legionalla sainthelensi, Legionalla tucsonensis and Legionalla wa
  • Cyclospora cayetanensis Entamoeba histolytica; Giardia lamblia; Trichomonas vaginalis; Toxoplasma gondii; Stenotrophomonas maltophilia; Burkholderia cepacia; Burkholderia mallei and Burkholderia pseudomallei; Francisella tularensis; Gardnerella (e.g. Gardneralla vaginalis and Gardneralla mobiluncus); Streptobacillus moniliformis; Flavobacteriaceae, such as Capnocytophaga (e.g.
  • Bartonella Bartonella ⁇ Bartonella bacilliformis, Bartonella clarridgeiae, Bartonella elizabethae, Bartonella henselae, Bartonella quintana and Bartonella vinsonii arupensis);
  • Leptospira e.g. Leptospira biflexa, Leptospira borgpetersenii, Leptospira inadai, Leptospira interrogans, Leptospira kirschneri, Leptospira noguchii, Leptospira santarosai and Leptospira wellii;
  • Spirillium e.g. Spirillum minus
  • Baceteroides e.g. Bacteroides caccae, Bacteroides capillosus, Bacteroides coagulans, Bacteroides distasonis, Bacteroides eggerthii, Bacteroides forsythus, Bacteroides fragilis, Bacteroides merdae, Bacteroides ovatus, Bacteroides putredinis, Bacteroides pyogenes, Bacteroides splanchinicus, Bacteroides stercoris, Bacteroides tectus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides ureolyticus and Bacteroides vulgatus); Prevotella (e.g. Bacteroides caccae, Bacteroides capillosus, Bacteroides coagulans, Bacteroides distasonis, Bacteroides eggerthii, Bacteroides forsythus, Bacteroides fragilis, Bacteroides
  • Porphyromonas e.g. Porphyromonas asaccharolytica, Porphyromonas cangingivalis, Porphyromonas canoris, Porphyromonas cansulci, Porphyromonas catoniae, Porphyromonas circumdentaria, Porphyromonas crevioricanis, Porphyromonas endodontalis, Porphyromonas gingivalis, Porphyromonas gingivicanis, Porphyromonas levii and Porphyromonas macacae);
  • Porphyromonas e.g. Porphyromonas asaccharolytica, Porphyromonas cangingivalis, Porphyromonas canoris, Porphyromonas cansulci, Porphyromonas catoniae, Porphyromonas circumdentaria, Porphyromonas crevioricanis, Porphyromonas endodontalis, Porphyromon
  • Fusobacterium e.g. F. gonadiaformans, F. mortiferum, F. naviforme, F. necrogenes, F. necrophorum necrophorum, F. necrophorum fundiliforme, F. nucleatum nucleatum, F. nucleatum fusiforme, F. nucleatum polymorphum, F. nucleatum vincentii, F. periodonticum, F. russii, F. ulcerans and F. varium);
  • Chlamydia e.g. Chlamydia trachomatis
  • Cryptosporidium e.g. C. parvum, C. hominis, C. canis, C. felis, C. meleagridis and C. muris
  • Chlamydophila e.g. Chlamydophila abortus (Chlamydia psittaci), Chlamydophila pneumoniae (Chlamydia pneumoniae) and Chlamydophila psittaci (Chlamydia psittaci)
  • Chlamydia abortus Chlamydia psittaci
  • Chlamydophila pneumoniae Chlamydia pneumoniae
  • Chlamydophila psittaci Chlamydophila psittaci
  • Leuconostoc e.g. Leuconostoc citreum, Leuconostoc cremoris, Leuconostoc dextranicum, Leuconostoc lactis, Leuconostoc mesenteroides and Leuconostoc pseudomesenteroides
  • Gemella e.g. Gemella bergeri, Gemella haemolysans, Gemella morbillorum and Gemella sanguinis
  • Ureaplasma e.g. Ureaplasma parvum and Ureaplasma urealyticum.
  • the bacterial infections treated by the combinations described herein are Gram- negative bacterial infections.
  • Particular Gram-negative bacteria that may be treated using a combination of the invention include:
  • Enterobacteriaceae such as Escherichia coli, Klebsiella (e.g. Klebs. pneumoniae and Klebs. oxytoca) and Proteus (e.g. Pr. mirabilis, Pr. rettgeri and Pr. vulgaris);
  • Klebsiella e.g. Klebs. pneumoniae and Klebs. oxytoca
  • Proteus e.g. Pr. mirabilis, Pr. rettgeri and Pr. vulgaris
  • Mycobacteria such as Mycobacterium tuberculosis
  • Enterobacter e.g. Enterobacter cloacae
  • the bacteria are Enterobacteriaceae, such as Escherichia coli, Klebsiella (e.g. Klebs. pneumoniae and Klebs. oxytoca) and Enterobacter (e.g. Enterobacter cloacae) and Acinetobacter spp.
  • Enterobacteriaceae such as Escherichia coli, Klebsiella (e.g. Klebs. pneumoniae and Klebs. oxytoca) and Enterobacter (e.g. Enterobacter cloacae) and Acinetobacter spp.
  • Escherichia coli, Klebsiella and Enterobacter e.g. Escherichia coli, Klebs. pneumoniae, Enterobacter cloacae and Acinetobacter spp, (e.g. Acinetobacter baumannii).
  • the combination of the present invention is particularly beneficial in treating (multi)-drug- resistant ((M)DR) bacteria.
  • MDR multi-drug- resistant
  • Enterobacteriaceae drug resistance most often builds up to carbapenemase i.e. carbapenemase-resistant strains and "extended spectrum ⁇ -lactamase" (ESBL) strains for example New Delhi Metallo-beta-lactamase-1 (NDM-1) resistant Klebs. Pneumonia, and NDM-1 E.coli.
  • the combinations of the present invention may be used to treat infections associated with any of the above-mentioned bacterial organisms, and in particular they may be used for killing multiplying and/or clinically latent microorganisms associated with such an infection, e.g. a Gram-negative bacterial infection.
  • Particular conditions which may be treated using the combination of the present invention include those which are caused by Gram-negative bacteria such as abscesses, asthma, bacilliary dysentry, bacterial conjunctivitis, bacterial keratitis, bacterial vaginosis, bone and joint infections, bronchitis (acute or chronic), brucellosis, burn wounds, cat scratch fever, cellulitis, chancroid, cholangitis, cholecystitis, cystic fibrosis, cystitis, nephritis, diffuse panbronchiolitis, dental caries, diseases of the upper respiratory tract, empymea, endocarditis, endometritis, enteric fever, enteritis, epididymitis, epiglottitis, eye infections, furuncles, gardnerella vaginitis, gastrointestinal infections (gastroenteritis), genital infections, gingivitis, gonorrhoea, granuloma inguinale,
  • opthalmia neonatorum osteomyelitis
  • otitis e.g. otitis externa and otitis media
  • orchitis pancreatitis, paronychia, pelveoperitonitis, peritonitis, peritonitis with appendicitis, pharyngitis, pleural effusion, pneumonia, postoperative wound infections, postoperative gas gangrene, prostatitis, pseudo-membranous colitis, psittacosis, pyelonephritis, Q fever, rat-bite fever, Ritter's disease, salmonellosis, salpingitis, septic arthritis, septic infections, septicameia, systemic infections, tonsillitis, trachoma, typhoid, urethritis, urinary tract infections, wound infections; or infections with, Escherichia coli, Klebs.
  • pneumoniae Klebs. oxytoca, Pr. mirabilis, Pr. rettgeri, Pr. vulgaris, Haemophilis influenzae, Enterococcus faecalis, Enterococcus faecium, and Enterobacter cloacae.
  • the polymyxin derivative is a compound of formula (I):
  • R1 is Dab
  • R2 is Thr
  • R3 is DThr
  • R4 is Dab
  • R5 is Dab
  • R6 is DPhe
  • R7 is Leu
  • R8 is Abu
  • R9 is Dab
  • R10 is Thr
  • R(FA) is octanoyl
  • R1 is absent
  • R2 is Thr
  • R3 is DSer
  • R4 is Dab
  • R5 is Dab
  • R6 is DPhe
  • R7 is Leu
  • R8 is Dab
  • R9 is Dab
  • R10 is Thr; and R(FA) is octanoyl; or pharmaceutically acceptable salts thereof.
  • the polymyxin derivatives of formula (I) are known compounds developed by Northern Antibiotics Oy.
  • the polymyxin derivative of formula (I) is NAB 815, wherein R1 is Dab; R2 is Thr; R3 is DThr; R4 is Dab; R5 is Dab; R6 is DPhe; R7 is Leu; R8 is Abu; R9 is Dab; R10 is Thr; and R(FA) is octanoyl.
  • the polymyxin derivative of formula (I) has R1-R10 representing an amino acid sequence Thr-DSer-cy[Dab-Dab-DPhe-Leu-Dab-Dab-Thr-].
  • the polymyxin derivative of formula (I) has R1-R10 representing SEQ ID NO. 2 defined herein.
  • SEQ ID NO.2 is Thr-DSer-cy[Dab-Dab-DPhe-Leu-Dab-Dab-Thr-].
  • SEQ ID NO.2 can also be written as Thr-DSer-[cyclo-Dbu-Dbu-DPhe-Leu-Dbu-Dbu-Thr] where Thr refers to Threonine; DSer refers to D-Serine; Dbu refers to 2,4-diaminobutyric acid; DPhe refers to D-Phenylalanine; Leu refers to Leucine and residues 3-9 form the cyclic heptapeptide portion.
  • polymyxin derivative of formula (I) has R1-R10 representing the amino acid sequence Dab-Thr-DThr-cy[Dab-Dab-DPhe-Leu-Abu-Dab-Thr-]. In one embodiment the polymyxin derivative of formula (I) has R1-R10 representing SEQ ID NO. 1 defined herein.
  • polymyxin derivative of formula (I) has R1-R10 representing SEQ ID N0.1 defined herein.
  • SEQ ID N0.1 is Dab-Thr-DThr-cy[Dab-Dab-DPhe-Leu-Abu-Dab-Thr-].
  • SEQ ID N0.1 can also be written as Dbu-Thr-DThr-[cyclo -Dbu-Dbu-DPhe-Leu-Abu-Dbu-Thr] where Thr refers to Threonine; Dbu refers to 2,4-diaminobutyric acid; DThr refers to D- Threonine; DPhe refers to D-Phenylalanine; Leu refers to Leucine; Abu refers to 2- aminobutyric acid; and residues 4-10 form the cyclic heptapeptide portion.
  • the polymyxin derivative of formula (I) can also be represented as OA-Thr-DSer-cy[Dab- Dab-DPhe-Leu-Dab-Dab-Thr-], i.e. OA-SEQ ID NO. 2 or as OA-Dab-Thr-DThr-cy[Dab-Dab- DPhe-Leu-Abu-Dab-Thr-], i.e. OA-SEQ ID NO. 1.
  • OA-SEQ ID NO. 1 is preferred.
  • Both NAB 815 and NAB 739 have a total number of positive charges at physiological pH of 3.
  • these positive charges are located at positions R5, R8 and R9 of formula (I), i.e. within the heptapeptide ring.
  • NAB 815 two of these positive charges are located within the heptapeptide ring at positions R5 and R9, and one is located on the hydrophobic tail at position R1.
  • pharmaceutically acceptable salt refers to salts with acids and bases which are known to be non-toxic and are commonly used in the pharmaceutical literature.
  • salts are acid addition salts including carboxylate salts (e.g. formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprate, caprylate, stearate, acrylate, caproate, propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate, a-hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate, phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxybenzoate, salicylate, nicotinate, isonicotinate, cinnamate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymaleate, hippurate, phthalate or
  • sulfonate salts e.g. benzenesulfonate, methyl-, bromo- or chloro- benzenesulfonate, xylenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate, hydroxyethanesulfonate, 1- or 2- naphthalene-sulfonate or 1 ,5-naphthalenedisulfonate salts) or sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate or nitrate salts, and the like.
  • sulfonate salts e.g. benzenesulfonate, methyl-, bromo- or chloro- benzenesulfonate, xylenesulfonate, methanes
  • a typically used acid for formation of the pharmaceutically acceptable salt of the polymyxin derivative of formula (I) is sulfuric acid.
  • pharmaceutically acceptable derivative means:
  • the at least one antibiotic resistance breaker (ARB) used in combination with the polymyxin derivative or pharmaceutically acceptable thereof is also a known compound and is typically commercially available or can be prepared by synthesis methods known in the art.
  • ARB antibiotic resistance breaker
  • mefloquine, mefloquine hydrochloride, zidovudine, suloctidil and phenoxybenzamine hydrochloride are commercially available from Sigma Aldrich Limited. Suitable dosages and formulations are also known in the art.
  • the at least one antibiotic resistance breaker combined with the polymyxin derivative of formula (I) or a pharmaceutically acceptable salt thereof is preferably zidovudine or a pharmaceutically acceptable derivative thereof.
  • Zidovudine is for example known as azidothymidine (AZT) and is an antiretroviral medication used to prevent and treat HIV/AIDs. It is generally recommended for use with other antiretrovirals and has the following chemical structure:
  • lUPAC name is l- ⁇ /i ⁇ S.SSJ- ⁇ Azido-S-ihydroxymethy oxolan ⁇ -yll-S-methylpyrimidine- 2,4-dione, and it is available by prescription only under the trade name Retrovir®. Zidovudine is preferably used in its non-salt form.
  • Suloctidil is a sulfur-containing aminoalcohol that was brought to market in the early 1970s as a vasodilator. It has the following chemical structure:
  • Suloctidil is preferably used in its non-salt form.
  • Mefloquine is an orally administered medication used in the prevention and treatment of malaria. It is commercially available in Europe under the trade name Lariam® in tablet form. Lariam® tablets include the hydrochloride salt of mefloquine and are indicated for the therapy and prophylaxis of malaria.
  • Mefloquine is a chiral molecule with two asymmetric carbon centres, which means that it has four different stereoisomers. Mefloquine is commercially available as a racemate of the (R,S)- and (S,R)-enantiomers
  • mefloquine includes all enantiomers, tautomers and stereoisomers thereof.
  • the corresponding enantiomers and/or tautomers may also be isolated/prepared by methods known in the art.
  • a preferred salt of mefloquine is the hydrochloride salt thereof, i.e. mefloquine hydrochloride.
  • Phenoxybenzamine is a non-selective, irreversible alpha blocker which is marketed under the trade name Dibenzyline®. It is used in the treatment of hypertension and has the following chemical structure:
  • Phenoxybenzamine is preferably used as the hydrochloride salt.
  • compositions of the invention include those suitable for parenteral (including subcutaneous e.g. by injection or by depot tablet, intravenous, intradermal, intrathecal, intramuscular e.g. by depot and intravenous), rectal, vaginal and topical (including dermal, buccal and sublingual) or in a form suitable for administration by inhalation or insufflation administration. The most suitable route of administration may depend upon the condition and disorder of the patient.
  • compositions of the present invention may also be in form of suppositories, pessaries, suspensions, emulsions, lotions, ointments, creams, gels, sprays, solutions or dusting powders.
  • transdermal administration is by use of a skin patch.
  • the active ingredients can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin.
  • the active ingredients can also be incorporated, at a concentration of between 1 and 10% by weight, into an ointment consisting of a white wax or white soft paraffin base together with such stabilisers and preservatives as may be required.
  • compositions of the invention are formulated for intravenous administration.
  • compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy e.g. as described in "Remington: The Science and Practice of Pharmacy", Lippincott Williams and Wlkins, 21 st Edition, (2005).
  • Suitable methods include the step of bringing into association the active ingredients with a carrier which constitutes one or more excipients.
  • compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • the active ingredients may be present in a concentration from 0.1 to 99.5% (such as from 0.5 to 95%) by weight of the total mixture; conveniently from 30 to 95% for tablets and capsules and 0.01 to 50% (such as from 3 to 50%) for liquid preparations.
  • doses employed for adult human treatment will typically be in the range of 0.02 to 5000 mg per day, preferably 1 to 1500 mg per day.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, e.g. as two, three, four or more sub-doses per day.
  • Test procedures that may be employed to determine the biological (e.g. bactericidal or antimicrobial) activity of the active ingredients include those known to persons skilled in the art for determining:
  • methods for determining activity against clinically latent bacteria include a determination, under conditions known to those skilled in the art (such as those described in Nature Reviews, Drug Discovery 1 , 895-910 (2002), the disclosures of which are hereby incorporated by reference), of Minimum Stationary-cidal Concentration (“MSC”) or Minimum Dormicidal Concentration (“MDC”) for a test compound.
  • MSC Minimum Stationary-cidal Concentration
  • MDC Minimum Dormicidal Concentration
  • WO2000028074 describes a suitable method of screening compounds to determine their ability to kill clinically latent bacteria.
  • a typical method may include the following steps:
  • the phenotypically resistant sub-population may be seen as representative of clinically latent bacteria which remain metabolically active in vivo and which can result in relapse or onset of disease.
  • methods for determining activity against log phase bacteria include a determination, under standard conditions (i.e. conditions known to those skilled in the art, such as those described in WO 2005014585, the disclosures of which document are hereby incorporated by reference), of Minimum Inhibitory Concentration ("MIC”) or Minimum Bactericidal Concentration (“MBC”) for a test compound.
  • MIC Minimum Inhibitory Concentration
  • MBC Minimum Bactericidal Concentration
  • Example 1 In vitro activity of zidovudine combined together with NAB739 and NAB815 against various Gram-negative bacteria using the chequerboard method The chequerboard method described in Antimicrob Chemo (2013) 68, 374-384 was carried out in Example 1 to investigate the in vitro activity of zidovudine combined together with NAB739 or NAB815 against various Gram-negative bacteria.
  • Zidovudine was obtained from a commercial source.
  • NAB815 was synthesized according to the method disclosed in Example 1 of WO20161 13470 (A1)
  • NAB739 was synthesized according to the method disclosed in Example 1 of WO2008017734 (A1).
  • the log phase bacterial cultures were incubated with each of the combinations overnight by diluting the cultures with nutrient broth (Oxoid) to 10 7 CFU/ml, and adding 280 ⁇ of each culture to each well to make a final concentration of 300 ⁇ . Incubation of the combinations with the bacterial suspensions was carried out for 24 hours.
  • the zidovudine concentration ranged from 64 mg/L to 1 mg/L and the compound concentrations ranged from 16 mg/L to 0.02 mg/L.
  • FICI fractional inhibitory concentration index
  • the interaction of the combination was defined as showing synergy if the FICI was ⁇ 0.5, no interaction if the FICI was >0.5 but ⁇ 4.0 and antagonism if the FICI was >4.0.
  • Antagonism >4 0 0
  • Antagonism >4 0 0
  • NDM-1 strains Synergy ⁇ 0.5 7 (100%) 7 (100%)
  • Antagonism >4 0 0
  • NDM-1 strains were Enterobacter cloacae (1 strain), E.coli (2 strains) and K.pneumoniae (4 strains).
  • the combination of zidovudine with NAB815 or NAB739 surprisingly exhibited synergistic activity against each of these drug-resistant strains.

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Abstract

La présente invention concerne une combinaison comprenant un dérivé de polymyxine de formule (I) définie dans la description, dans laquelle R1 est Dab ; R2 est Thr ; R3 est DThr ; R4 est Dab ; R5 est Dab ; R6 est DPhe ; R7 est Leu ; R8 est Abu ; R9 est Dab ; R10 est Thr ; et R(FA) est un octanoyle ; ou où R1 est absent ; R2 est Thr ; R3 est DSer ; R4 est Dab ; R5 est Dab ; R6 est DPhe ; R7 est Leu ; R8 est Dab ; R9 est Dab ; R10 est Thr ; et R(FA) est un octanoyle ; ou des sels pharmaceutiquement acceptables de celui-ci; et au moins un agent de rupture de résistance aux antibiotiques choisi dans le groupe constitué par la zidovudine, la suloctil, la méfloquine, la phénoxybenzamine ou un dérivé pharmaceutiquement acceptable de celles-ci. L'invention concerne également l'utilisation de cette combinaison dans le traitement d'infections bactériennes, de préférence des infections bactériennes Gram négatif, en particulier des infections bactériennes Gram négatif résistantes aux médicaments.
PCT/GB2018/050577 2017-03-23 2018-03-07 Combinaisons de polymyxines WO2018172733A1 (fr)

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