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WO2016021695A1 - Agent antibactérien - Google Patents

Agent antibactérien Download PDF

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Publication number
WO2016021695A1
WO2016021695A1 PCT/JP2015/072400 JP2015072400W WO2016021695A1 WO 2016021695 A1 WO2016021695 A1 WO 2016021695A1 JP 2015072400 W JP2015072400 W JP 2015072400W WO 2016021695 A1 WO2016021695 A1 WO 2016021695A1
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WO
WIPO (PCT)
Prior art keywords
antibacterial agent
carbon atoms
alkyl group
dif
formula
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Ceased
Application number
PCT/JP2015/072400
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English (en)
Japanese (ja)
Inventor
禅 久保原
大島　吉輝
晴久 菊池
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gunma University NUC
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Gunma University NUC
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Publication date
Application filed by Gunma University NUC filed Critical Gunma University NUC
Publication of WO2016021695A1 publication Critical patent/WO2016021695A1/fr
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N35/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical
    • A01N35/04—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having two bonds to hetero atoms with at the most one bond to halogen, e.g. aldehyde radical containing aldehyde or keto groups, or thio analogues thereof, directly attached to an aromatic ring system, e.g. acetophenone; Derivatives thereof, e.g. acetals
    • 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
    • A61K31/12—Ketones

Definitions

  • the present invention relates to a novel antibacterial agent and a pharmaceutical composition containing the antibacterial agent as an active ingredient.
  • slime mold The cellular slime mold Dictyostelium discoideum (hereinafter referred to as slime mold) is a lower eukaryote that inhabits the fallen leaves of the forest and forms a fruiting body (consisting of spores and stems) that resembles mold.
  • slime molds and fungi are a group of organisms that are evolutionarily far apart. The present inventors have focused on slime molds and have actually reported some drug candidate substances.
  • slime molds are being studied as “model organisms of developmental biology / cell biology” for various cell functions.
  • the slime mold cells germinated from the spore grow as a single cell amoeba using surrounding bacteria as food. When there is no food, it becomes a signal, and the cells gather to form a multicellular body (consisting of about 100,000 cells), and finally a fruiting body.
  • Several low molecular weight compounds are known as physiologically active factors that control the generation and differentiation of slime molds.
  • DIF-1 Differentiation-inducing factor-1
  • Non-patent Documents 1 and 2 Differentiation-inducing factor-1
  • DIF-3 isolated at the same time has low differentiation-inducing activity and is known to be a degradation product of DIF-1 (Non-patent Documents 3, 4, and 5).
  • DIF-1 and DIF-3 are originally slime mold differentiation-inducing factors that induce differentiation of slime molds themselves, and compounds isolated as degradation products thereof.
  • DIF-1, DIF-3 (hereinafter collectively referred to as DIF compounds) and their derivatives (hereinafter sometimes referred to as DIF derivatives), in mammalian cells, inhibit tumor cell growth and promote glucose metabolism It has been discovered that it has activity, interleukin-2 production control activity, and further has growth inhibitory activity against Trypanosoma protozoa (Patent Documents 1 to 5). On the other hand, antibacterial activity against bacteria was only examined for DIF-1, but the MIC value for S.
  • This invention makes it a subject to provide a novel antibacterial agent.
  • the present inventors have conducted intensive studies to solve the above problems. In other words, we examined the effects of DIF compounds and various DIF derivatives on the growth of several bacterial strains (including multidrug-resistant bacteria MRSA) and found that DIF compounds and DIF derivatives strongly inhibit bacterial growth in vitro. As a result, it was found that an antibacterial agent meeting the above-mentioned problems was achieved, and the present invention was completed.
  • An antibacterial agent comprising a compound represented by the following general formula (I) or (II) or a salt thereof.
  • R 1 represents hydrogen, an alkyl group having 1 to 10 carbon atoms or a phenyl group
  • R 2 represents hydrogen or an alkyl group having 1 to 10 carbon atoms
  • X 1 represents hydrogen or halogen.
  • R 1 represents hydrogen, an alkyl group having 2 to 10 carbon atoms or a phenyl group
  • R 2 represents hydrogen or an alkyl group having 1 to 10 carbon atoms
  • X 1 and X 2 are independently Indicates hydrogen or halogen.
  • An antibacterial pharmaceutical composition comprising the antibacterial agent according to any one of [1] to [6].
  • a method for inhibiting bacterial growth comprising the step of adding an effective amount for inhibiting bacterial growth to the sample containing bacteria.
  • the compound represented by the formula (I) or (II) can be suitably used as an antibacterial agent against bacteria belonging to the genus Staphylococcus and Bacillus.
  • Antibacterial agent comprises a compound represented by the following general formula (I) or (II) (hereinafter sometimes referred to as a compound of formula (I) or a compound of formula (II)) or a salt thereof. It relates to antibacterial agents.
  • R 1 represents hydrogen, an alkyl group having 1 to 10 carbon atoms, or a phenyl group
  • R 2 represents hydrogen, an alkyl group having 1 to 10 carbon atoms
  • X 1 represents hydrogen or halogen.
  • R 1 represents hydrogen, a linear, branched or cyclic alkyl group or phenyl group having 1 to 10 carbon atoms, preferably an alkyl or phenyl group having 1 to 6 carbon atoms, more preferably carbon.
  • An alkyl or phenyl having 2 to 6 carbon atoms is preferable, and an alkyl group or phenyl group having 4 to 5 carbon atoms is more preferable.
  • R 2 represents hydrogen, a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms, preferably an alkyl group having 5 to 10 carbon atoms, more preferably an alkyl group having 6 to 8 carbon atoms.
  • X 1 represents hydrogen or halogen. Halogen includes chlorine (Cl), bromine (Br), iodine (I), etc., preferably Cl.
  • R 1 represents hydrogen, an alkyl group having 2 to 10 carbon atoms, or a phenyl group
  • R 2 represents hydrogen, an alkyl group having 1 to 10 carbon atoms
  • X 1 and X 2 are independently Indicates hydrogen or halogen.
  • R 1 represents hydrogen, a linear, branched or cyclic alkyl group or phenyl group having 2 to 10 carbon atoms, preferably an alkyl or phenyl group having 2 to 6 carbon atoms, more preferably carbon.
  • R 2 represents hydrogen, a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms, preferably an alkyl group having 5 to 10 carbon atoms, more preferably an alkyl group having 6 to 8 carbon atoms.
  • X 1 and X 2 independently represent hydrogen or halogen. Halogen includes chlorine (Cl), bromine (Br), iodine (I), etc., preferably Cl.
  • the compound of the above formula (I) or (II) can be synthesized by the method described in, for example, Biochem. Pharmacol. 2005, 70, or 676-685.
  • the compound of formula (I) or (II) or a salt thereof has an effect of inhibiting the growth of bacteria such as Gram-positive bacteria belonging to the genus Staphylococcus, Bacillus and the like. Therefore, it can be used as antibacterial agents, antibiotics, antibiotics, active ingredients of antibacterial pharmaceutical compositions, laboratory reagents, daily necessities and the like.
  • the antibacterial pharmaceutical composition includes not only a drug that cures symptoms caused by bacteria, but also a drug that improves symptoms and a drug that prevents symptoms.
  • a pharmaceutically acceptable salt can be used, and examples thereof include metal salts such as sodium, potassium, magnesium, and calcium, and ammonium salts.
  • the compound of formula (I) or (II) may be a hydrate.
  • the “antibacterial agent” includes a drug that reduces the number of bacteria, a drug that suppresses the increase (growth) of the number of bacteria, a drug that inactivates bacteria, and the like.
  • “inactivating bacteria” includes reducing or suppressing the ability of bacteria to regenerate, and examples of inactivating means include killing.
  • the antibacterial agent of the present invention can also be used in combination with an antibacterial agent other than the compound of formula (I) or (II) or a salt thereof.
  • composition relates to an antibacterial pharmaceutical composition containing an antibacterial agent comprising the compound of formula (I) or (II) or a salt thereof.
  • the “antibacterial agent” of the present invention can be used as an antibacterial pharmaceutical composition.
  • the antibacterial pharmaceutical composition is a gram-positive bacterium belonging to the genus Staphylococcus, Bacillus, Clostridium, Propionic acid, Micrococcus, Streptococcus, Peptococcus, Lactobacillus, Actinomyces, Streptomyces, etc. It can be used for infectious diseases caused by bacteria.
  • Staphylococcus aureus is preferably mentioned.
  • the bacterium belonging to the genus Bacillus is preferably Bacillus subtilis.
  • the subject to which the antibacterial pharmaceutical composition of the present invention is administered is an animal infected with bacteria or an animal developing an infection caused by bacteria.
  • animals include not only humans but also non-human animals such as livestock, poultry, laboratory animals, pets (competing animals), and the like.
  • the non-human animals of the present invention include domestic animals such as cows, horses, pigs, goats and sheep, poultry such as chickens, ducks, geese, turkeys and quails, mice, rats, guinea pigs, dogs, monkeys, fishes and the like.
  • pets such as animals, dogs, cats and birds.
  • the subject of administration can be administered prophylactically to animals that are likely to be infected with bacteria, in addition to animals that have been infected with bacteria as described above or that have developed infections with bacteria.
  • a pharmaceutical composition comprising a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof is prepared according to the known means generally used in the production of pharmaceutical preparations,
  • the pharmaceutically acceptable salt is mixed as it is or with a pharmacologically acceptable carrier, for example, tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules (soft capsules Including), liquids, injections, suppositories, sustained-release preparations and the like, and can be safely administered orally or parenterally (eg, topical, rectal, intravenous administration, etc.).
  • Examples of pharmacologically acceptable carriers include excipients, lubricants, binders and disintegrants in solid formulations, or solvents, solubilizers, suspending agents, isotonic agents, buffers in liquid formulations. And soothing agents. If necessary, additives such as conventional preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
  • examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.
  • Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • binder examples include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like.
  • disintegrant examples include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, and the like.
  • solvent examples include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, Examples thereof include hydrophilic polymers such as sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose.
  • Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
  • Examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like.
  • Examples of soothing agents include benzyl alcohol.
  • Examples of the preservative include parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Examples of the antioxidant include sulfite, ascorbic acid, ⁇ -tocopherol and the like.
  • the antibacterial pharmaceutical composition of the present invention may be used in combination with other drugs.
  • the content of the compound of formula (I) or (II) or a salt thereof in the antibacterial pharmaceutical composition is about 0.01 to about 100% by weight of the whole preparation.
  • the dose of the compound of formula (I) or a salt thereof varies depending on the administration subject, target organ, symptom, administration method, etc., and is not particularly limited, but is generally about 1 day per day for a patient (with a body weight of 60 kg).
  • the amount is 0.1 to 5 g, preferably about 0.1 to 1 g, more preferably about 0.1 to 0.5 g.
  • Example 1 Examination of the effect on S. aureus Staphylococcus aureus (209P strain) and S. aureus (MRSA: multidrug resistant strain or MS29202 strain: Gunma University graduate School of Medicine attached research facility for drug resistant bacteria)
  • MRSA multidrug resistant strain or MS29202 strain: Gunma University graduate School of Medicine attached research facility for drug resistant bacteria
  • DIF compounds and various DIF derivatives and commercially available antibacterial agents penicillin / streptomycin, impenem, gentamicin, levofloxacin, clindamycin
  • MRSA pre-cultured on agar medium, solvent (2 ⁇ L each) or drug (DIF compound and DIF derivative: 10 mM solution each 2 ⁇ L / disc, penicillin / streptomycin : 1U ⁇ 1 ⁇ g / disc, Impenem: 10 ⁇ g / disc, Gentamicin: 10 ⁇ g / disc, Levofloxacin: 5 ⁇ g / disc, Clindamycin: 2 ⁇ g / disc) Culturing was carried out at 20 ° C. for 20 hours.
  • Penicillin / streptomycin was effective in the wild strain but almost ineffective in the resistant strain. Clindamycin, impenem, gentamicin, and levofloxacin were also ineffective in resistant strains.
  • DIF-1 was effective in both wild and resistant strains. DIF derivatives were also effective against resistant strains. This methicillin resistant strain is also resistant to many antibacterial agents (clindamycin, impenem, gentamicin, levofloxacin), but DIF compounds and various DIF derivatives were effective against this resistant strain, It is considered useful as a new antibacterial agent.
  • MIC minimum inhibitory concentration
  • Staphylococcus aureus (209P strain) and S. aureus MRSA: multi-drug resistant strain or MS29202 strain: Gunma University
  • MRSA multi-drug resistant strain or MS29202 strain: Gunma University
  • MIC value antibacterial activity of DIF compounds and various DIF derivatives was examined and measured for ATCC6633 strain (the above is Gram positive bacteria) and Escherichia coli (NIHJ strain) (Gram negative bacteria) as follows. Suspend each bacterium in Müller Hinton S medium (10 7 cells / ml: the medium is light yellow and almost transparent due to low bacterial concentration). Dispense 100 ⁇ l of this suspension into a 96-well plate (round bottom). did.
  • the antibacterial activity MIC value ( ⁇ M) of DIF compounds and various DIF derivatives are shown in Table 1 below.
  • the tested DIF compounds and various DIF derivatives are found to have antibacterial activity against Staphylococcus aureus and / or Bacillus subtilis.
  • the MIC value of vancomycin in clinically isolated enterococci in Japan is usually 1 ⁇ g / ml (about 0.7 ⁇ M) or less (National Institute of Infectious Diseases infection information center: http: //idsc.nih.go. jp / disease / vre / vre02.html).
  • MICs of vancomycin are recognized as low-resistant bacteria with 4-8 ⁇ g / ml and MICs of 16 ⁇ g / ml or more as resistant bacteria.
  • MRSA S. aureus
  • the present invention is useful in the medical field.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Agronomy & Crop Science (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Plant Pathology (AREA)
  • Epidemiology (AREA)
  • Dentistry (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un agent antibactérien constitué d'un composé, représenté par la formule générale (I) ou (II), ou d'un sel de celui-ci. Dans la formule (I), R1 représente un atome d'hydrogène, un groupe alkyle comportant de 1 à 10 atomes de carbone ou un groupe phényle ; R2 représente un atome d'hydrogène ou un groupe alkyle comportant de 1 à 10 atomes de carbone ; et X1 représente un atome d'hydrogène ou un atome d'halogène. Dans la formule (II), R1 représente un atome d'hydrogène, un groupe alkyle comportant de 2 à 10 atomes de carbone ou un groupe phényle ; R2 représente un atome d'hydrogène ou un groupe alkyle comportant de 1 à 10 atomes de carbone ; et chacun des X1 et X2 représente, indépendamment, un atome d'hydrogène ou un atome d'halogène.
PCT/JP2015/072400 2014-08-06 2015-08-06 Agent antibactérien Ceased WO2016021695A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2014160596A JP6478378B2 (ja) 2014-08-06 2014-08-06 抗菌剤
JP2014-160596 2014-08-06

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WO2016021695A1 true WO2016021695A1 (fr) 2016-02-11

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7565603B2 (ja) * 2019-03-06 2024-10-11 学校法人順天堂 マラリア原虫の増殖抑制剤

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001021164A2 (fr) * 1999-09-22 2001-03-29 Advanced Life Sciences, Inc. Compositions anti-mycobacterium, procedes de preparation et d'utilisation associes

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001021164A2 (fr) * 1999-09-22 2001-03-29 Advanced Life Sciences, Inc. Compositions anti-mycobacterium, procedes de preparation et d'utilisation associes

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
BONIFAIT, LAETITIA ET AL.: "Synthesis and antimicrobial activity of geranyloxy- and farnesyloxy-acetophenone derivatives against oral pathogens", FITOTERAPIA, vol. 83, no. 6, pages 996 - 999, XP028427379, DOI: doi:10.1016/j.fitote.2012.06.003 *
FRIEDMAN, MENDEL ET AL.: "Antibacterial activities of phenolic benzaldehydes and benzoic acids against Campylobacter jejuni, Escherichia coli, Listeria monocytogenes, and Salmonella enterica", J. FOOD PROT., vol. 66, no. 10, 2003, pages 1811 - 1821, XP008123125 *
NGAN, LUONG THI MY ET AL.: "Growth-inhibiting, bactericidal, and urease inhibitory effects of Paeonia lactiflora root constituents and related compounds on antibiotic-susceptible and -resistant strains of Helicobacter pylori", J. AGRIC. FOOD CHEM, vol. 60, 31 August 2012 (2012-08-31), pages 9062 - 9073 *
PELTTARI, EILA ET AL.: "Antimicrobial properties of substituted salicylaldehydes and related compounds", Z. NATURFORSCH., vol. 62c, 2007, pages 487 - 497 *
PELTTARI, EILA ET AL.: "Substituted salicylaldehydes as potential antimicrobial drugs: minimal inhibitory and microbicidal concentrations", Z. NATURFORSCH., vol. 66c, 2011, pages 571 - 580 *
RAMOS-NINO, M. E. ET AL.: "QSARs for the effect of benzaldehydes on foodborne bacteria and the role of sulfhydryl groups as targets of their antibacterial activity", J. APPL MICROBIOL., vol. 84, 1998, pages 207 - 212, XP003017735, DOI: doi:10.1046/j.1365-2672.1998.00324.x *
REHN, D. ET AL.: "Zur antimiKrobiellen wirksamkeit substituierter aromatischer aldehyde(About the antimicrobial activity of substituted aromatic aldehydes", ZBL. BAKT. HYG., I. ABT. ORIG. B, vol. 172, 1981, pages 508 - 19 *

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JP6478378B2 (ja) 2019-03-06
JP2016037456A (ja) 2016-03-22

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