WO2024242056A1 - 環状ペプチド化合物とそれを含む抗菌剤 - Google Patents

環状ペプチド化合物とそれを含む抗菌剤 Download PDF

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Publication number
WO2024242056A1
WO2024242056A1 PCT/JP2024/018354 JP2024018354W WO2024242056A1 WO 2024242056 A1 WO2024242056 A1 WO 2024242056A1 JP 2024018354 W JP2024018354 W JP 2024018354W WO 2024242056 A1 WO2024242056 A1 WO 2024242056A1
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Prior art keywords
compound
ddd
group
nmr
mmol
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English (en)
French (fr)
Japanese (ja)
Inventor
元三 田邉
文洋 石川
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Kindai University
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Kindai University
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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
    • A61K38/15—Depsipeptides; Derivatives thereof
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods
    • 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

Definitions

  • the present invention relates to cyclic peptide compounds that have high antibacterial activity against bacteria.
  • Non-Patent Document 1 Non-Patent Document 2
  • the mechanism of action is based on the following:
  • the ADEP side chain has an electrophilic reactive group, ⁇ , ⁇ -unsaturated carbonyl, which is found in many covalent drugs.
  • the present invention was conceived in light of the above problems, and by conducting SAR research on the side chain, we created a highly active derivative with improved metabolic stability, resulting in a new antibacterial agent.
  • cyclic peptide compound according to the present invention is a cyclic peptide compound having the structure of formula (1).
  • R1 is any of a phenyl group, a naphthyl group, a cyclohexyl group, an adamantane group, a C3-C18 linear alkyl group, and a phenyl group in which any hydrogen has been substituted (the substituted functional group is at least one of a C3-C18 linear alkyl group, a C1-C3 alkoxyl group, a halogen group, a C1-C3 perfluoroalkyl group, a nitro group, a trifluoromethoxy group, and a cyclopentyl group).
  • Antibacterial tests were performed using the positive control ADEP1, compound 1, and this compound group against B. subtilis ATCC6051, Staphylococcus epidermidis ATCC12228, and B. cereus ATCC11778, with the following results.
  • 1 shows a reaction scheme of a cyclic peptide compound according to the present invention. 1 is a known reaction scheme showing the synthesis of the starting material for the cyclic peptide compound of the present invention.
  • the present invention is a cyclic peptide compound having the structure of the following formula (1).
  • R1 is any of the following: phenyl group, naphthyl group, cyclohexyl group, adamantane group, C3-C18 linear alkyl group, and phenyl group in which any hydrogen has been substituted (the substituted functional group is at least one of C3-18 linear alkyl group, C1-C3 alkoxyl group, halogen group, C1-C3 perfluoroalkyl group, nitro group, trifluoromethoxy group, and cyclopentyl group).
  • C represents carbon, and the number after C indicates the number of carbons.
  • the cyclic peptide compound of formula (1) is a new substance obtained through SAR research using compound 1 shown in formula (2) as the parent compound.
  • Compound 1 was chosen as the parent compound because it is easy to synthesize, is one of the synthetic compounds that exhibits high activity, and has a track record of being used as a positive control in many studies.
  • the cyclic peptide compound of the present invention was synthesized by expanding the structure of the side chain portion of compound 1 to produce compound 1 derivatives with different side chain structures.
  • the cyclic peptide compound according to the present invention can be synthesized by the reaction scheme shown in Figure 1. In other words, it can be obtained by a coupling reaction between the synthesized compound (23) and an isocyanate having a functional group R1 bonded thereto.
  • Compound (23) (see Figure 1) was synthesized by the method disclosed in Non-Patent Document 4. The reaction scheme is shown in Figure 2. Referring to Figure 2, the compound (23) is obtained when R is hydrogen in the substance (S6).
  • the cyclic peptide compound according to the present invention can be produced by a step of coupling reaction of compound (23) with an isocyanate having a functional group R1.
  • the present invention can also provide an antibacterial agent containing at least one of the above compounds as an active ingredient.
  • the antibacterial agent of the present invention can be administered by intravenous, subcutaneous, or intramuscular injection.
  • the antibacterial agent of the present invention may be formulated into an external preparation such as a liquid, ointment, cream, gelling agent, patch, or aerosol, and administered parenterally.
  • water, lower alcohol, solubilizing agent, surfactant, emulsion stabilizer, gelling agent, adhesive, and other necessary base components can be blended.
  • additives such as vasodilators, adrenal cortical hormones, keratolytic agents, moisturizers, bactericides, antioxidants, cooling agents, fragrances, and colorants may be appropriately blended.
  • the numbers in formula (3) indicate functional group numbers, where functional group 1 is a phenyl group, functional group 2 is a naphthyl group, functional group 3 is a tolyl group, functional group 4 is an ethylphenyl group, functional group 5 is a butylphenyl group, functional group 6 is a p-methoxyphenyl group, functional group 7 is an ethoxyphenyl group, functional group 8 is a fluorophenyl group, functional group 9 is a chlorophenyl group, functional group 10 is a trifluorophenyl group, functional group 11 is a nitrophenyl group, functional group 12 is an acetophenyl group, functional group 13 is a C3 linear alkyl group, functional group 14 is a C4 linear alkyl group, functional group 15 is a C6 linear alkyl group, functional group 16 is a C7 linear alkyl group, functional group 17 is a C12 linear alkyl group, functional group 18 is a C18 linear
  • each functional group in formula (3) is R1 in formula (1)
  • compounds (1) to (22) and compound (24) are referred to as compounds (1) to (22) and compound (24), respectively.
  • the compounds are distinguished by the numbers of the functional groups.
  • EtOAc stands for ethyl acetate
  • EtOH stands for ethanol.
  • the synthesis procedures for each compound are shown below.
  • the compound (1) was subjected to 1 H-NMR, 13 C-NMR and mass spectrometry (high-resolution electrospray ionization mass spectrometry, HR-ESI-MS) measurements, and the results are shown below.
  • the compound (2) was subjected to 1 H-NMR, 13 C-NMR and mass spectrometry (high-resolution electron spray ionization nmass spectrometry, HR-ESI-MS) measurements, and the results are shown below.
  • the compound (3) was subjected to 1 H-NMR, 13 C-NMR and mass spectrometry (high-resolution electron spray ionization nmass spectrometry, HR-ESI-MS) measurements, and the results are shown below.
  • the compound (4) was subjected to 1 H-NMR, 13 C-NMR and mass spectrometry (high-resolution electron spray ionization nmass spectrometry, HR-ESI-MS) measurements, and the results are shown below.
  • the compound (5) was subjected to 1 H-NMR, 13 C-NMR and mass spectrometry (high-resolution electron spray ionization nmass spectrometry, HR-ESI-MS) measurements, and the results are shown below.
  • the compound (6) was subjected to 1 H-NMR, 13 C-NMR and mass spectrometry (high-resolution electron spray ionization nmass spectrometry, HR-ESI-MS) measurements, and the results are shown below.
  • the compound (7) was subjected to 1 H-NMR, 13 C-NMR and mass spectrometry (high-resolution electron spray ionization nmass spectrometry, HR-ESI-MS) measurements, and the results are shown below.
  • the compound (8) was subjected to 1 H-NMR, 13 C-NMR and mass spectrometry (high-resolution electron spray ionization nmass spectrometry, HR-ESI-MS) measurements, and the results are shown below.
  • the compound (9) was subjected to 1 H-NMR, 13 C-NMR and mass spectrometry (high-resolution electron spray ionization nmass spectrometry, HR-ESI-MS) measurements, and the results are shown below.
  • the compound (10) was subjected to 1 H-NMR, 13 C-NMR and mass spectrometry (high-resolution electron spray ionization nmass spectrometry, HR-ESI-MS) measurements, and the results are shown below.
  • the compound (11) was subjected to 1 H-NMR, 13 C-NMR and mass spectrometry (high-resolution electron spray ionization nmass spectrometry, HR-ESI-MS) measurements, and the results are shown below.
  • the compound (12) was subjected to 1 H-NMR, 13 C-NMR and mass spectrometry (high-resolution electron spray ionization nmass spectrometry, HR-ESI-MS) measurements, and the results are shown below.
  • the compound (13) was subjected to 1 H-NMR, 13 C-NMR and mass spectrometry (high-resolution electron spray ionization nmass spectrometry, HR-ESI-MS) measurements, and the results are shown below.
  • the compound (14) was subjected to 1 H-NMR, 13 C-NMR and mass spectrometry (high-resolution electron spray ionization nmass spectrometry, HR-ESI-MS) measurements, and the results are shown below.
  • the compound (15) was subjected to 1 H-NMR, 13 C-NMR and mass spectrometry (high-resolution electron spray ionization nmass spectrometry, HR-ESI-MS) measurements, and the results are shown below.
  • the compound (16) was subjected to 1 H-NMR, 13 C-NMR and mass spectrometry (high-resolution electron spray ionization nmass spectrometry, HR-ESI-MS) measurements, and the results are shown below.
  • the compound (17) was subjected to 1 H-NMR, 13 C-NMR and mass spectrometry (high-resolution electron spray ionization nmass spectrometry, HR-ESI-MS) measurements, and the results are shown below.
  • the compound (18) was subjected to 1 H-NMR, 13 C-NMR and mass spectrometry (high-resolution electron spray ionization nmass spectrometry, HR-ESI-MS) measurements, and the results are shown below.
  • the compound (19) was subjected to 1 H-NMR, 13 C-NMR and mass spectrometry (high-resolution electron spray ionization nmass spectrometry, HR-ESI-MS) measurements, and the results are shown below.
  • the compound (20) was subjected to 1 H-NMR, 13 C-NMR and mass spectrometry (high-resolution electron spray ionization nmass spectrometry, HR-ESI-MS) measurements, and the results are shown below.
  • the compound (21) was subjected to 1 H-NMR, 13 C-NMR and mass spectrometry (high-resolution electron spray ionization nmass spectrometry, HR-ESI-MS) measurements, and the results are shown below.
  • the compound (22) was subjected to 1 H-NMR, 13 C-NMR and mass spectrometry (high-resolution electron spray ionization nmass spectrometry, HR-ESI-MS) measurements, and the results are shown below.
  • the compound (24) was subjected to 1 H-NMR, 13 C-NMR and mass spectrometry (high-resolution electrospray ionization mass spectrometry, HR-ESI-MS) measurements, and the results are shown below.
  • ADEP1 has a structure represented by formula (4).
  • the general formulas of compound 1 (formula (2)) and the compounds of the present invention (formulas (1) and (2), and the functional group portions of compounds (1) to (22) and (24) (formula (3)) are also shown below.
  • the unit is ( ⁇ g/mL)
  • compounds (3), (4), (5), (6), (7), and (9) exhibited 32-fold, 128-fold, 4-fold, 4-fold, and 16-fold higher antibacterial activity than ADEP1.
  • Compounds (3), (4), and (9) also exhibited 6-fold, 26-fold, and 3-fold higher antibacterial activity than compound 1.
  • compounds (5), (6), and (7) exhibited the same level of antibacterial activity as compound 1.
  • compound (3) exhibited 32 times higher antibacterial activity than ADEP1.
  • Compound (3) also exhibited 2 times higher antibacterial activity than compound 1.
  • compound (6) is the position of the methoxy group bonded to the benzene ring (meta vs. para), but since they have almost the same antibacterial activity, it is believed that the position of the terminal functional group bonded to the phenyl group has almost no effect on antibacterial activity.
  • the cyclic peptide compound according to the present invention has an antibacterial effect against various bacteria and can be provided as an antibacterial agent. Furthermore, by utilizing the cyclic peptide compound according to the present invention in cell biology, molecular biology, and biochemistry research, it is not only useful as a research tool for elucidating the protein degradation system in microorganisms, but also as a drug discovery seed with a new mechanism of action.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
PCT/JP2024/018354 2023-05-22 2024-05-17 環状ペプチド化合物とそれを含む抗菌剤 Ceased WO2024242056A1 (ja)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005510468A (ja) * 2001-09-19 2005-04-21 バイエル・ヘルスケア・アクチェンゲゼルシャフト 抗菌性マクロ環
WO2015031871A1 (en) * 2013-08-30 2015-03-05 St. Jude Children's Research Hospital Substituted urea depsipeptide analogs as activators of the clpp endopeptidase
WO2016141351A1 (en) * 2015-03-04 2016-09-09 St. Jude Children's Research Hospital Substituted urea depsipeptide analogs as activators of the clpp endopeptidase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005510468A (ja) * 2001-09-19 2005-04-21 バイエル・ヘルスケア・アクチェンゲゼルシャフト 抗菌性マクロ環
WO2015031871A1 (en) * 2013-08-30 2015-03-05 St. Jude Children's Research Hospital Substituted urea depsipeptide analogs as activators of the clpp endopeptidase
WO2016141351A1 (en) * 2015-03-04 2016-09-09 St. Jude Children's Research Hospital Substituted urea depsipeptide analogs as activators of the clpp endopeptidase

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