WO2022121977A1 - 稠环酚类化合物的药学应用 - Google Patents

稠环酚类化合物的药学应用 Download PDF

Info

Publication number
WO2022121977A1
WO2022121977A1 PCT/CN2021/136707 CN2021136707W WO2022121977A1 WO 2022121977 A1 WO2022121977 A1 WO 2022121977A1 CN 2021136707 W CN2021136707 W CN 2021136707W WO 2022121977 A1 WO2022121977 A1 WO 2022121977A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
bacterial infection
ppk
composition
pharmaceutically acceptable
Prior art date
Application number
PCT/CN2021/136707
Other languages
English (en)
French (fr)
Inventor
吉祥
Original Assignee
润佳(苏州)医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 润佳(苏州)医药科技有限公司 filed Critical 润佳(苏州)医药科技有限公司
Priority to US18/266,331 priority Critical patent/US20240131001A1/en
Priority to CN202180081162.0A priority patent/CN116568297A/zh
Priority to CA3201759A priority patent/CA3201759A1/en
Priority to EP21902682.0A priority patent/EP4260854A1/en
Priority to AU2021394410A priority patent/AU2021394410A1/en
Publication of WO2022121977A1 publication Critical patent/WO2022121977A1/zh

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/3533,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365Lactones
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365Lactones
    • A61K31/366Lactones having six-membered rings, e.g. delta-lactones
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/38Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/38Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/39Heterocyclic compounds having sulfur as a ring hetero atom having oxygen in the same ring
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/70Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • YGENERAL 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
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the use of a fused-ring phenolic compound, or a pharmaceutically acceptable salt or ester thereof, in the preparation of a medicament for treating, inhibiting or preventing bacterial infection.
  • the present invention relates to a PPK inhibitor.
  • Pseudomonas aeruginosa alias Pseudomonas aeruginosa, a Gram-negative bacterial pathogen
  • Pseudomonas aeruginosa "alias Pseudomonas aeruginosa, a Gram-negative bacterial pathogen” was an urgently needed antibiotic. "First Class Priority" pathogens. Pseudomonas aeruginosa is one of the most important acquired pathogens in the hospital setting and is susceptible to infecting patients with compromised immune systems (eg, cystic fibrosis, cancer or AIDS patients, etc.) and those requiring medical equipment such as respiratory aids and catheters of patients.
  • compromised immune systems eg, cystic fibrosis, cancer or AIDS patients, etc.
  • Pseudomonas aeruginosa can also cause other very serious and fatal infections (such as pneumonia, urinary and gastrointestinal infections, etc.). Pseudomonas aeruginosa is resistant to many high-efficiency antibiotics currently used, such as carbapenems and cephalosporins. In the face of the rapid development of drug resistance in bacterial pathogens, the research and development of antibiotic drugs has been seriously lagging behind.
  • Polyphosphate is a chain-like inorganic compound composed of several to hundreds of phosphoric acid groups connected by high-energy phosphoric anhydride bonds, and widely exists in all living organisms. Studies have shown that polyP will accumulate in bacteria under unfavorable living conditions, making bacteria highly tolerant to environmental stress. ), etc. together respond to stress and are considered to be global regulators of stress and toxicity response pathways in numerous bacterial species. Specifically, PPK is required for Pseudomonas aeruginosa quorum sensing, biofilm formation, toxin secretion, and virulence in animal infection models.
  • Inorganic polyphosphate is a linear polymer formed by the polymerization of inorganic phosphate monomers through high-energy phosphoric acid bonds, and the length can reach 1000 monomers.
  • polyphosphates are synthesized and consumed by polyphosphate kinases. These enzymes are further divided into two main families, polyphosphate kinase-1 (PPK1) and polyphosphate kinase-2 (PPK2).
  • the PPK1 enzyme preferentially uses ATP as a phosphorylating agent to catalyze the synthesis of polyphosphates.
  • PPK1 As a key virulence determinant of Pseudomonas aeruginosa, and demonstrated that after PPK1 gene knockout, Pseudomonas aeruginosa's quorum sensing, Motility, biofilm formation, and virulence are all severely affected (Polyphosphate kinase is essential for biofilm development, quorum sensing, and virulence of Pseudomonas aeruginosa. PNAS. 97, 9636–9641).
  • PPK2 enzymes that do not have any similarity in sequence to PPK1, and their main function is to use polyP to synthesize GTP instead of polyP.
  • PPK2 has been identified in many species, including major pathogens, as a determinant of virulence and persistence in Pseudomonas aeruginosa, highlighting the overall importance of polyP balance during bacterial infection.
  • PPKs have been hailed as potential targets for antimicrobial therapy.
  • the current screening effort has identified several inhibitors of the PPK1 and PPK2 enzymes, resulting in several compounds with relatively weak activity against PPK1 and PPK2 based on bisphosphonates (Burda-Grabowska, M. et al, Bisphosphonic acids and related compounds as inhibitors of nucleotide-and polyphosphate-processing enzymes: A PPK1and PPK2case study.Chem Biol Drug Des.10.1111/cbdd.13439).
  • potent compounds low micromolar or nanomolar activity
  • the technical problem mainly solved by this application is to provide potent compounds against PPK.
  • the applicant found that a specific fused-ring phenolic compound, or a pharmaceutically acceptable salt or ester thereof, can effectively inhibit the production of PPK enzyme, thereby preparing a medicament for treating, inhibiting or preventing bacterial infection.
  • the present invention provides the use of a fused-ring phenolic compound in the preparation of a medicament for treating, inhibiting or preventing bacterial infection, wherein the fused-ring phenolic compound comprises one or more compounds in Table 1 or its A pharmaceutically acceptable salt or ester.
  • the bacterial infection comprises a bacterial infection caused by bacteria that produce one or more polyphosphokinases (PPKs).
  • PPK includes, for example, PPK1, PPK2A, PPK2B, and PPK2C.
  • the bacterial infection described above comprises infection by Pseudomonas aeruginosa, Klebsiella Pneumoniae, Escherichia coli, Staphylococcus aureus, salmonella, Bacillus subtilis Infections caused by Bacillus subtilis, Acinetobacter baumannii, Enterobacter cloacae or Enterococcus.
  • the Enterococcus is a vancomycin-resistant Enterococcus
  • the Staphylococcus aureus is a Methicillin-resistant Staphylococcus aureus.
  • the above bacterial infection comprises a bacterial infection caused by Pseudomonas aeruginosa.
  • C, H, O and S atoms in the above compounds are each independently selected from naturally abundant atoms and isotopically enriched atoms.
  • the isotopically enriched atoms are selected from the group consisting of 12 C, 13 C and 14 C of carbon; 1 H, 2 H and 3 H of hydrogen; 16 O, 17 O and 18 O of oxygen; and 32S , 33S and 34S of sulfur.
  • the compounds of the present invention may be the listed compounds as well as pharmaceutically acceptable salts or esters, and may also be pharmaceutically acceptable prodrug compounds.
  • the present invention provides a medicament comprising one or more of the compounds of the present invention for the treatment, inhibition or prevention of bacterial infection, wherein the bacterial infection comprises a bacterial infection associated with a PPK enzyme-catalyzed reaction.
  • the present invention relates to the use of a composition in the preparation of a medicament for the treatment, inhibition or prevention of bacterial infection, wherein the composition comprises a compound as defined in this application and at least one pharmaceutically acceptable carrier or thinner.
  • the above-mentioned drug is a PPK inhibitor for the treatment, inhibition or prevention of bacterial infections caused by bacteria that produce one or more polyphosphokinases (PPKs); wherein the bacterial infections include green Infections caused by Pseudomonas, Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, Salmonella, Bacillus subtilis, Acinetobacter baumannii, Enterobacter cloacae, or Enterococcus.
  • the Enterococcus is a vancomycin-resistant Enterococcus
  • the Staphylococcus aureus is a Methicillin-resistant Staphylococcus aureus.
  • the above bacterial infection comprises a bacterial infection caused by Pseudomonas aeruginosa.
  • the aforementioned pharmaceutically acceptable carriers or diluents include creams, emulsions, gels, liposomes, or nanoparticles.
  • the present invention provides the use of a kit in the preparation of a medicament for treating, inhibiting or preventing bacterial infection, wherein the kit comprises a compound of the present application or a pharmaceutically acceptable salt or ester or the present invention composition; and diluents (eg, sterile water), buffers, pharmaceutically acceptable excipients.
  • diluents eg, sterile water
  • the present invention provides a method for inhibiting bacterial growth in vitro, wherein the bacteria are selected from Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, Salmonella, Bacillus subtilis, and Acinetobacter baumannii , Enterobacter cloacae or Enterococcus, preferably Pseudomonas aeruginosa.
  • the method comprises: administering a compound in Table 1 above, or a pharmaceutically acceptable salt or ester thereof, or a composition of the present application or a kit of the present application, to bacteria at an effective concentration or amount.
  • the specific fused-ring phenolic compounds provided in this application, or their pharmaceutically acceptable salts or esters, can be used to effectively inhibit the production of PPK enzymes, especially for Pseudomonas aeruginosa and other bacteria that are regulated by PPK enzyme catalysis.
  • the infection has a strong effect, so that a drug for treating, inhibiting or preventing bacterial infection can be prepared, and an excellent therapeutic, inhibiting or preventive effect can be obtained.
  • Figure 1 IC50 plot of compound 4 for inhibition of different PPKs (PPK1, PPK2A, PPK2B and PPK2C).
  • Figure 2 Effect of compound 4 on biofilm formation in different Pseudomonas aeruginosa strains: A, absorbance; experimental concentration of compound 4 was 100 ⁇ M, "-" or "+” means no or addition of compound 4; WT, wild strain ; ⁇ ppk1 is the PPK1 knockout strain; ⁇ ppk2A ⁇ ppk2B ⁇ ppk2C is the PPK2A, PPK2B, PPK2C knockout strain; ⁇ ppk1 ⁇ ppk2A ⁇ ppk2B ⁇ ppk2C is the PPK1, PPK2A, PPK2B, PPK2C knockout strain.
  • Figure 3 Effect of compound 4 on survival of Pseudomonas aeruginosa infected nematodes.
  • Figure 4 Toxicity test of compound 4 and compound B on human embryonic kidney cells (HEK cells): relative viability of cells in the presence of DMSO (control), compound B (100 ⁇ M), and compound 4 (100 ⁇ M).
  • derivative as used in the present invention should be understood as another compound which is similar in structure but differs in some fine structure.
  • the present invention provides the use of a fused-ring phenolic compound, or a pharmaceutically acceptable salt or ester thereof, in the preparation of a medicament for treating, inhibiting or preventing bacterial infection, the fused-ring phenolic compound.
  • the class of compounds is selected from, but not limited to, the compounds listed in Table 1.
  • “Pharmaceutically acceptable salt” of a compound refers to a salt of a pharmaceutically acceptable compound. Salts of desired compounds (basic, acidic, or charged functional groups) can retain or improve the biological activity and properties of the parent compound as defined herein, and are not biologically undesirable.
  • the compounds provided herein may contain unnatural proportions of isotopic atoms at one or more of the atoms that constitute such compounds.
  • Unnatural proportions of isotopes can be defined as amounts ranging from those found in nature to those consisting of 100% of the atoms in question.
  • compounds can incorporate radioactive isotopes such as tritium ( 3 H) or carbon-14 ( 14 C) or non-radioactive isotopes such as deuterium ( 2 H) or carbon-13 ( 13 C).
  • radioactive isotopes such as tritium ( 3 H) or carbon-14 ( 14 C) or non-radioactive isotopes such as deuterium ( 2 H) or carbon-13 ( 13 C).
  • isotopic changes may provide additional applications to those described elsewhere in this application.
  • isotopic variants of the compounds of the present invention may find additional uses, including but not limited to, as diagnostic and/or imaging agents, or as cytotoxic/radiotoxic therapeutics.
  • isotopic variants may have altered pharmacokinetic and pharmacodynamic profiles that may contribute to enhanced safety, tolerability or efficacy during treatment. All isotopic variations of the compounds provided herein, whether radioactive or not, are encompassed by the present invention.
  • naturally abundant element or “naturally abundant atom” refers to the element or atom, respectively, of its most abundant atomic mass in nature.
  • the natural abundance of hydrogen is 1 H
  • the natural abundance of sulfur is 32 S
  • the natural abundance of oxygen is 16 O
  • the natural abundance of carbon is 12 C
  • a "non-isotopically enriched" compound is one in which all atoms or elements in the compound are isotopes in natural abundance, ie all atoms or elements are most abundant in atomic mass in nature.
  • the fused-ring phenolic compounds disclosed in the present application, or pharmaceutically acceptable salts or esters thereof, have a good inhibitory effect on one or both of PPK1 and PPK2, and are used for the preparation of therapeutic, inhibiting or preventing bacterial infections. drug.
  • the bacterial infection includes PPK-related bacterial infection, which may be PPK1-related bacterial infection, PPK2-related bacterial infection, or both PPK1 and PPK2-related bacterial infection.
  • PPK-associated bacterial infection and "PPK-mediated bacterial infection” are used interchangeably to refer to any bacterial infection, disease, disorder or condition that would benefit from treatment with a PPK inhibitor.
  • PPK-related bacterial infections encompass those infections caused by bacteria/pathogens that carry at least one or more of the PPKs.
  • infections or “bacterial infection” include the presence of bacteria in or on a subject that would benefit the subject if the growth of the bacteria was inhibited.
  • infection or “bacterial infection” refers to the undesired normal flora in addition to the presence of bacteria.
  • infection includes infections referred to by bacteria. Examples of such bacterial infections include many important bacterial pathogens such as P. aeruginosa, K.
  • Pseudomonas aeruginosa can encode not only three PPK2 enzymes, namely PPK2A (PA14_01730), PPK2B (PA14_33240) and PPK2C (PA14_19410), but also PPK1 (PA14_69230).
  • the bacterial infection may be an infection caused by Pseudomonas aeruginosa, or by Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, Salmonella, Bacillus subtilis, Acinetobacter baumannii, Enterobacter cloacae Bacillus, vancomycin-resistant Enterococcus, or methicillin-resistant Staphylococcus aureus.
  • growth refers to the growth of one or more microorganisms, and includes the reproduction or population expansion of microorganisms such as bacteria.
  • the term also includes metabolic processes that maintain a microorganism on-going, including processes that keep the microorganism alive.
  • the fused-ring phenolic compound provided by the present invention can be used as a PPK inhibitor, and the PPK inhibitor can simultaneously inhibit PPK1 and PPK2, or can inhibit either of them.
  • the fused-ring phenolic compounds of the present invention function to inhibit PPK activity and/or anti-inflammatory activity, and are useful as therapeutic or prophylactic therapeutics when such inhibition is desired. Unless otherwise indicated, when the use of the compounds of the present invention is described herein, it is to be understood that these compounds may be in the form of a composition (ie, a pharmaceutical composition).
  • PPK inhibitor As used herein, the terms “PPK inhibitor”, “PPK blocker”, “polyphosphokinase inhibitor”, “polyphosphokinase inhibitor” and all other related art acceptable terms are used interchangeably to represent compounds that directly or indirectly inhibit PPK receptors in in vitro assays, in vivo models, and/or in other assays that demonstrate PPK inhibition and potential therapeutic or prophylactic efficacy. The term also refers to compounds that exhibit at least some therapeutic or prophylactic benefit in human subjects.
  • the present invention also provides a bacteriostatic agent/drug for treating, inhibiting or preventing bacterial infection, especially bacterial infection associated with PPK, comprising one or more of the above compounds, wherein the bacterial infection comprises a bacterial infection caused by Pseudomonas aeruginosa Bacillus, Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, Salmonella, Acinetobacter baumannii, Bacillus subtilis, Enterobacter cloacae, or Enterococcus.
  • bacteriostatic agent refers to the ability to inhibit, reduce or prevent the growth of bacteria, inhibit or reduce the ability of bacteria to cause infection in a subject, or inhibit or reduce the ability of bacteria to reproduce or maintain infection in the environment, or reduce the infectivity of bacteria or virulence of any substance, compound or combination thereof.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: a compound disclosed in the present invention or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising at least one of Compounds 1 to 10, or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier.
  • the present invention provides the use of at least one PPK inhibitor compound or composition provided by the present invention for the treatment and/or prevention of immune-related diseases, disorders and conditions, diseases with an inflammatory component, and diseases associated with The above related methods of dissonance.
  • treating refers to initiating action (eg, administration of a PPK inhibitor or a pharmaceutical composition comprising the same) after a disease, disorder or condition, or symptoms thereof, has been diagnosed, observed, to temporarily or permanently eliminate, alleviate, inhibit , alleviating or ameliorating at least one underlying cause of the disease, disorder, or condition afflicting the subject, or symptoms associated with the disease, disorder, or condition afflicting the subject.
  • treatment includes inhibiting (eg, preventing or ameliorating the development or further development of a disease, disorder or condition or clinical symptoms associated therewith) active disease.
  • treatment as used herein is used to specifically mean the administration of a therapeutic comprising a compound or composition according to the present invention to a patient already suffering from an infection.
  • treatment also relates to administering a compound or composition according to the invention, optionally together with one or more antibacterial agents, to: alleviate or alleviate a bacterial infection or one or more symptoms associated with a bacterial infection; or slowing the development of a bacterial infection or one or more symptoms associated with a bacterial infection; or reducing the severity of a bacterial infection or one or more symptoms associated with a bacterial infection; or inhibiting the clinical manifestations of a bacterial infection; or Suppresses the manifestation of adverse symptoms of bacterial infection.
  • prevention refers to initiating action (e.g., administration of a PPK inhibitor or a pharmaceutical composition comprising the same) in a manner (e.g., prior to the onset of a disease, disorder, condition, or symptoms thereof), thereby temporarily or permanently preventing, inhibiting , suppress or reduce a subject's risk of developing a disease, disorder or condition, etc. (as determined by, eg, lack of clinical symptoms) or delay the onset of a particular disease, condition or condition in the case of a subject predisposed to it.
  • the term also refers to slowing the progression of a disease, disorder or condition or inhibiting its progression into a deleterious or other undesirable state.
  • the term “prophylaxis” as used herein is used to refer to the administration of a compound or composition according to the present invention to prevent infection caused by bacteria or to prevent the occurrence of related infections and/or diseases.
  • prevention also encompasses the prevention of at least one bacterial infection by administration of a compound or composition according to the invention by administering to a patient susceptible to or at risk of bacterial infection.
  • the present invention further provides the use of the PPK inhibitor compounds and compositions described herein in combination with one or more additional agents.
  • the one or more additional agents may have some PPK-modulating activity and/or they may act through different mechanisms of action.
  • such agents comprise radiation (eg, local radiation therapy or systemic radiation therapy) and/or other treatment modalities that are not pharmacological in nature.
  • the PPK inhibitor and one additional agent may be in a single composition or in multiple compositions, and the treatment modality may be administered simultaneously, sequentially or by some other regimen.
  • the radiation phase is followed by a chemotherapy phase.
  • Combination therapy can have additive or synergistic effects.
  • compositions containing the active ingredient may be in a form suitable for oral use, such as tablets, capsules, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions , hard or soft capsules, or syrup, solution, microbeads, or elixir.
  • Pharmaceutical compositions for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents such as sweetening, flavoring, coloring and a preservative to provide a pharmaceutically acceptable formulation.
  • Tablets, capsules and the like generally contain the active ingredient in admixture with non-toxic pharmaceutically acceptable carriers or excipients which are suitable for the manufacture of tablets.
  • carriers or excipients can be, for example, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binders, such as starch, gelatin Or gum arabic and lubricants such as magnesium stearate, stearic acid or talc.
  • the composition is an injectable formulation. In other embodiments, the composition is formulated for oral administration to a subject.
  • compositions are contained in single-use containers (eg, single-use vials, ampoules, syringes, or auto-injectors), while in other embodiments, multiple-use containers (eg, multiple used vials).
  • single-use containers eg, single-use vials, ampoules, syringes, or auto-injectors
  • multiple-use containers eg, multiple used vials
  • the formulations may also include carriers to protect the composition from rapid degradation or disappearance from the body, such as controlled release formulations, including liposomes, hydrogels, and microencapsulated delivery systems.
  • controlled release formulations including liposomes, hydrogels, and microencapsulated delivery systems.
  • time delay materials such as glyceryl monostearate or glyceryl stearate alone or in combination with waxes can be used.
  • Any drug delivery device can be used to deliver the PPK inhibitor, including implants (eg, implantable pumps) and catheter systems, slow infusion pumps and devices. All of these are well known to those skilled in the art.
  • compositions may also be in the form of sterile injectable aqueous or oily suspensions.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned herein.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • solvents and dispersion media that may be used are water, Ringer's solution, isotonic sodium chloride solution, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS), ethanol, polyol Alcohols such as glycerol, propylene glycol and liquid polyethylene glycols and suitable mixtures thereof.
  • sterile fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables. Prolonged absorption of the specific injectable formulations can be brought about by the inclusion of agents which delay absorption, for example, aluminum monostearate or gelatin.
  • the PPK inhibitor compounds and compositions provided herein can be administered to a subject in any suitable manner known in the art.
  • Suitable routes of administration include, but are not limited to, oral; parenteral, eg, intramuscular, intravenous, subcutaneous (eg, injection or implantation), intraperitoneal, intracisternal, intraarticular, intracerebral (intraparenchymal and intraventricular; nasal cavity ; vaginal; sublingual; intraocular; rectal; topical (eg, transdermal); buccal and inhalation.
  • Depot injection typically by subcutaneous or intramuscular administration, can also be used to release the PPK inhibitors disclosed herein over a defined period of time .
  • kits comprising PPK inhibitor compounds or compositions.
  • the kits are generally in the form of physical structures containing the various components, and can be used, for example, to practice the methods provided herein.
  • a kit can include one or more PPK inhibitors disclosed herein (e.g., provided in a sterile container) in the form of a pharmaceutical composition suitable for administration to a subject.
  • the PPK inhibitor may be provided in ready-to-use (eg, tablet or capsule) form or in a form that requires reconstitution or dilution (eg, powder), eg, prior to administration.
  • the kit may also include diluents (eg, sterile water), buffers, pharmaceutically acceptable excipients, etc.
  • diluents eg, sterile water
  • the kit may contain several therapeutic agents independently, or they may already be combined in the kit.
  • Each component of the kit can be packaged in a separate container, and all of the various containers can be in a single package.
  • the kits of the present invention can be designed to properly maintain the conditions required (eg, refrigerated or frozen) for the components contained therein.
  • Compound 1 was synthesized using 2-bromo-3,4,5-trimethoxybenzoic acid (2.67 g, 9.17 mmol) as starting material.
  • Compound 6 was a commercial product purchased from Shanghai Yuanye Biotechnology Co., Ltd.
  • Compound 7 was a commercial product purchased from Shanghai Yuanye Biotechnology Co., Ltd.
  • Compound 8 is a commercial product purchased from Bailingwei.
  • Compound 9 is a commercial product from Aldrich.
  • compound 10 was synthesized starting from thiophen-3-ylboronic acid.
  • Compound A is a commercial product purchased from Bailingwei.
  • This compound can also be purchased from commercial channels, and the compound used in this application is synthesized according to the following reaction:
  • the compound was synthesized from 2-methoxybenzene-1,3-diol as the starting material.
  • the compound was synthesized from 6-bromo-2,3-dimethoxybenzoic acid as starting material.
  • the compound was synthesized using resorcinol as the starting material.
  • the compound was synthesized from 1,3-dioxo-1,3-dihydroisobenzofuran-5-carboxylic acid as starting material.
  • Compound F is a commercial product from Aldrich.
  • Compound G is a commercial product from Aldrich.
  • Compound H is a commercial product from TCI.
  • Pseudomonas aeruginosa can produce biofilms in the culture medium.
  • group A was inoculated with wild Pseudomonas aeruginosa (WT)
  • group B was inoculated with PPK1 knockout Pseudomonas aeruginosa ( ⁇ ppk1)
  • group C was inoculated with knockout PPK2A
  • Pseudomonas aeruginosa ⁇ ppk2A, ⁇ ppk2B, ⁇ ppk2C
  • group D was inoculated with Pseudomonas aeruginosa ( ⁇ ppk1, ⁇ ppk2, A ⁇ ppk2B, ⁇ ppk2C) that knocked out PPK1 and PPK2A, PPK2B, and PPK2C at the same time.
  • each group was divided into two groups, one of which was added with DMSO (-) as a control, and the other was added with 100 ⁇ m of compound 4 (+).
  • the bacteria were cultured at 37°C for 24 hours, and a layer of biofilm would grow in the medium.
  • the biofilms in the four groups of medium A, B, C, and D were analyzed with 570 nm visible light, and the results showed: Compound 4 It has a good inhibitory effect on wild Pseudomonas aeruginosa and can reduce the formation of biofilm; and the compound can not only inhibit PPK1, but also has a good inhibitory effect on PPK2.
  • the specific results are shown in Figure 2.
  • C. elegans were divided into five groups, A, B, C, D, and E, and then modeled respectively.
  • groups A and B were infected with wild-type (WT) Pseudomonas aeruginosa, in which group A was the DMSO control group, and group B was the compound 4 treatment group;
  • groups C and D received knockout of all PPK ( ⁇ polyP, namely ⁇ ppk1 ⁇ ppk2A ⁇ ppk2B ⁇ ppk2C) Infection of Pseudomonas aeruginosa, group C was the DMSO control group, group D was the compound 4 treatment group;
  • group E was the control group to receive Escherichia coli (OP50E.coli) infection.
  • the cytotoxicity of the compounds was evaluated in cultured human embryonic kidney cells (HEK 239T) by trypan blue viability assay, and the blank solvent DMSO, compound B and compound 4 were tested respectively.
  • the test results are shown in Figure 4. The results showed that Compound 4 was not cytotoxic (close to 100% relative viability) at concentrations up to 100 ⁇ M, while Compound B caused substantial cell death (approximately 35% relative viability).
  • fused-ring phenolic compounds disclosed in this application not only have strong activity, but also have safety (low or no cytotoxicity); and have good inhibitory effects on both PPK1 and PPK2. Therefore, it is feasible for such compounds to be used in the preparation of medicaments for the treatment, inhibition or prevention of bacterial infections associated with PPK.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

一种稠环酚类化合物,或其药学上可接受的盐或酯,在制备用于治疗、抑制或预防细菌感染的药物中的用途。本发明公开的稠环酚类化合物,可以抑制PPK1和PPK2,并可用于治疗绿脓杆菌等细菌引起的感染或病症。

Description

稠环酚类化合物的药学应用
相关申请的交叉引用
本申请基于申请号为202011453853.2、申请日为2020年12月09日的中国专利申请提出,并要求该中国专利申请的优先权,该中国专利申请的全部内容在此引入本申请作为参考。
技术领域
本发明涉及一种稠环酚类化合物,或其药学上可接受的盐或酯,在制备用于治疗、抑制或预防细菌感染的药物中的用途。具体的,本发明涉及一种PPK抑制剂。
背景技术
世界卫生组织和发达国家认为,耐抗生素病原体对全球健康、粮食安全、和全球发展等具有严重威胁。抗药性细菌病原体对医疗系统的影响巨大。2015年,加拿大公共卫生局公开了由此造成的社会经济、生产力、和医疗保健等方面的成本和支出,至少在10亿美元。2016年“英国抗生素耐药性评估报告”认为,抗生素耐药性将对经济产生严重威胁。该评估报告认为,到2050年,抗生素耐药性将导致全球GDP下降2-3.5%,相当于100兆美元的直接经济损失。该报告还指出,如果对抗生素耐药性问题不加以关注,全球每年将有1000万人死于耐药性细菌病原体的感染。
2017年2月,世界卫生组织首次发表了抗生素耐药的“优先病原体”名单,并宣布绿脓杆菌(Pseudomonas aeruginosa,别名铜绿假单胞菌,是一种革兰氏阴性细菌病原体)是急需抗生素的“一类优先”病原体。绿脓杆菌是医院环境中最主要的获得性病原体之一,并容易感染那些免疫系统受损的 患者(如囊性纤维化、癌症或艾滋病患者等)以及那些需要诸如呼吸辅助及导管等医疗设备的患者。绿脓杆菌还会导致其它非常严重以及致命的感染(如肺炎、尿路感染和胃肠道感染等)。绿脓杆菌对目前使用的诸如碳青霉烯类和头孢菌素类等众多高效抗生素具有抗药性。面对细菌病原体耐药性的迅速发展,抗生素药物的研究和开发已经严重滞后。
多聚磷酸盐(PolyP)是由几个到上百个磷酸基团组成并由高能磷酸酐键连接的链状无机化合物,广泛地存在于所有生命体中。研究表明,polyP在不适宜的生存条件下会在菌体内聚集,使细菌对环境压力有极强的耐受性,它与其相关的多聚磷酸盐激酶(PPK)、外切聚磷酸酶(PPX)等一起作出应激反应,被认为是众多细菌物种中应激和毒性反应途径的全局调节器。具体来说,PPK是绿脓杆菌定额传感、生物膜形成、毒素分泌和动物感染模型中的毒力所必需的。无机多聚磷酸盐(polyP)是无机磷酸盐单体通过高能磷酸键聚合而成的线性多聚体,长度可达1000个单体。在细菌中,多聚磷酸盐由多磷酸激酶合成和消耗。这些酶又分为两个主要家族,多聚磷酸盐激酶-1(PPK1)和多聚磷酸盐激酶-2(PPK2)。PPK1酶优先使用ATP作为磷酸化剂催化多聚磷酸盐的合成,Arthur Kornberg首次确定PPK1是绿脓杆菌的关键毒力决定因素,并且证明了PPK1基因敲除后,绿脓杆菌的定额传感、运动性、生物膜形成和毒力都受到严重影响(Polyphosphate kinase is essential for biofilm development,quorum sensing,and virulence of Pseudomonas aeruginosa.PNAS.97,9636–9641)。许多细菌除了PPK1以外,还具有在序列上与PPK1没有任何相似性的PPK2酶,其主要功能是利用polyP合成GTP而不是合成polyP。PPK2已在包括主要病原体在内的许多物种中得以鉴定,在绿脓杆菌中作为毒性和持久性的决定因素,突出了细菌感染过程中polyP平衡的总体重要性。
鉴于PPK酶在细菌发病过程中的重要性,以及哺乳动物中缺乏同源酶,PPKs被誉为抗菌疗法的潜在靶点。目前的筛选工作已经发现了几种PPK1 和PPK2酶的抑制剂,基于双膦酸盐产生了几种针对PPK1和PPK2的活性相对较弱的化合物(Burda-Grabowska,M.et al,Bisphosphonic acids and related compounds as inhibitors of nucleotide-and polyphosphate-processing enzymes:A PPK1and PPK2case study.Chem Biol Drug Des.10.1111/cbdd.13439)。然而,针对这两类PPK的强效化合物(低微摩尔或纳摩尔活性)尚未被报道。
发明内容
本申请主要解决的技术问题是提供针对PPK的强效化合物。申请人发现特定的稠环酚类化合物,或其药学上可接受的盐或酯能够有效抑制PPK酶产生,从而制备用于治疗、抑制或预防细菌感染的药物。
一方面,本发明提供了稠环酚类化合物在制备用于治疗、抑制或预防细菌感染的药物中的用途,其中,该稠环酚类化合物包括表1中的一种或多种化合物或其药学上可接受的盐或酯。
表1:稠环酚类化合物
Figure PCTCN2021136707-appb-000001
Figure PCTCN2021136707-appb-000002
优选地,所述细菌感染包括由产生一种或多种多磷酸激酶(PPK)的细菌所引起的细菌感染。具体地,PPK例如包括PPK1、PPK2A、PPK2B和PPK2C。
在一些实施例中,上述细菌感染包括由绿脓杆菌(Pseudomonas aeruginosa)、肺炎克雷伯菌(Klebsiella Pneumoniae)、大肠杆菌(Escherichia coli)、金黄葡萄球菌(Staphylococcus aureus)、沙门氏菌(salmonella)、枯草芽孢杆菌(Bacillus subtilis)、鲍曼不动杆菌(Acinetobacter baumannii)、阴沟肠杆菌(Enterobacter cloacae)或肠球菌(Enterococcus)引起的感染。在一些具体实施例中,肠球菌为耐万古霉素的肠球菌,金黄葡萄球菌为耐甲氧西林的金葡菌。
在一尤其优选的实施例中,上述细菌感染包括由绿脓杆菌所引起的细菌感染。
进一步地,上述化合物中的C、H、O和S原子各自独立选自天然丰度的原子和同位素丰度富集的原子。
进一步地,同位素富集的原子选自碳的 12C、 13C和 14C;选自氢的 1H、 2H和 3H;选自氧的 16O、 17O和 18O;以及选自硫的 32S、 33S和 34S。
此外,本发明的化合物可以是所列化合物以及药学上可接受的盐或酯, 也可以是药学上可接受的前体药物化合物。
又一方面,本发明提供一种用于治疗、抑制或预防细菌感染的药物,包括本发明的化合物中的一种或多种,其中所述细菌感染包括与PPK酶催化反应有关的细菌感染。
再一方面,本发明涉及一种组合物在制备用于治疗、抑制或预防细菌感染的药物中的用途,其中,所述组合物包括本申请所限定的化合物以及至少一种可药用的载体或稀释剂。
在一些实施例中,上述药物为PPK抑制剂,用于治疗、抑制或预防由产生一种或多种多磷酸激酶(PPK)的细菌所引起的细菌感染;其中,所述细菌感染包括由绿脓杆菌、肺炎克雷伯菌、大肠杆菌、金黄葡萄球菌、沙门氏菌、枯草芽孢杆菌、鲍曼不动杆菌、阴沟肠杆菌或肠球菌所引起的感染。如上所述,一些具体实施例中,肠球菌为耐万古霉素的肠球菌,金黄葡萄球菌为耐甲氧西林的金葡菌。
在尤其优选的实施例中,上述细菌感染包括由绿脓杆菌所引起的细菌感染。
在一些实施例中,上述可药用的载体或稀释剂包括乳膏、乳剂、凝胶、脂质体或纳米颗粒。
再一方面,本发明提供了试剂盒在制备用于治疗、抑制或预防细菌感染的药物中的用途,其中,所述试剂盒包括本申请的化合物或药学上可接受的盐或酯或者本发明的组合物;以及稀释剂(例如无菌水)、缓冲液、药学上可接受的赋形剂。
又一方面,本发明提供了体外抑制细菌生长的方法,其中,所述细菌选自绿脓杆菌、肺炎克雷伯菌、大肠杆菌、金黄葡萄球菌、沙门氏菌、枯草芽孢杆菌、鲍曼不动杆菌、阴沟肠杆菌或肠球菌,优选绿脓杆菌。所述方法包括:将上表1中的化合物或其药学上可接受的盐或酯或者本申请的 组合物或者本申请的试剂盒以有效浓度或有效量施用至细菌。
本申请提供的特定的稠环酚类化合物,或其药学上可接受的盐或酯,能够用于有效地抑制PPK酶的产生,尤其针对绿脓杆菌等通过PPK酶催化进行调节的细菌引发的感染具有很强的效果,从而制备治疗、抑制或预防细菌感染的药物,并取得优异的治疗、抑制或预防效果。
附图说明
图1:化合物4抑制不同PPK(PPK1、PPK2A、PPK2B和PPK2C)的IC 50曲线图。
图2:化合物4对不同绿脓杆菌菌株中的生物膜形成的影响:A,吸光度;化合物4的实验浓度为100μM,“-”或“+”表示不添加或添加化合物4;WT,野生菌株;Δppk1,为PPK1敲除菌株;Δppk2AΔppk2BΔppk2C为PPK2A、PPK2B、PPK2C敲除菌株;Δppk1Δppk2AΔppk2BΔppk2C为PPK1、PPK2A、PPK2B、PPK2C敲除菌株。
图3:化合物4对受绿脓杆菌感染的线虫的生存率的影响。
图4:化合物4和化合物B对人胚胎肾细胞(HEK cell)的毒性实验:细胞在DMSO(对照)、化合物B(100μM)、和化合物4(100μM)存在时的相对存活率。
具体实施方式
为了对本发明的说明书中所使用的术语提供清楚且一致的理解,在下文中提供一些定义。此外,除了特殊说明,本发明所用的全部技术和科学术语具有同本发明所属领域中普通技术人员通常所理解的相同的含义。
当在权利要求和/或说明书中与术语“包括”结合使用时,词语“一”的使用可以表示“一个”,但它也与“一个或多个”,“至少一个”和“一个或多于一个”的含义已知。类似地,词语“另一个”可以表示至少第二个或者很多个。
如在本说明书和权利要求中所使用的词语“包括”(以及包括的任何形式,诸如“包括”和“包含”),“具有”(以及任何形式的具有,“具有”、“包含”和“含有”)是包括性的和开放式的,并且不排除另外的未列出的要素或处理步骤。术语“约”或“大约”用于表示该值包括在确定该值中所用的仪器和方法带来的误差。
本发明所用的术语“衍生物”应理解为是结构上类似,在一些细微结构上不同的另一种化合物。
在一实施方式中,本发明提供了一种稠环酚类化合物,或其药学上可接受的盐或酯,在制备用于治疗、抑制或预防细菌感染的药物中的用途,该稠环酚类化合物选自但不限于表1所列化合物。
化合物的“药学上可接受的盐”是指药学上可接受的化合物的盐。理想的化合物的盐(碱性、酸性或带电官能团)可以保留或改善如本发明所定义的母体化合物的生物活性和性质,并且不是生物学上不需要的。
在一实施方式中,本发明提供的化合物可以在构成此类化合物的一个或多个原子处含有非天然比例的同位素原子。同位素的非天然比例可以定义为从自然界中发现的量到由所讨论的原子的100%构成的量。例如,化合物可以并入放射性同位素,例如氚( 3H)或碳-14( 14C)或非放射性同位素如氘( 2H)或碳-13( 13C)。这种同位素变化可以为本申请中其它地方描述的那些提供额外的应用。例如,本发明化合物的同位素变体可以找到额外的用途,包括但不限于作为诊断和/或成像试剂,或作为细胞毒性/放射性毒性治疗剂。另外,同位素变体可以具有改变的药代动力学和药效学特征,其可以有助于增强治疗期间的安全性,耐受性或疗效。本发明提供的化合物的所有同位素变体,无论是否是放射性的,均涵盖在本发明中。
本发明所用术语“天然丰度元素”或“自然丰度原子”分别是指其在自然界中最丰富的原子质量的元素或原子。例如,氢的天然丰度元素为 1H,硫 的天然丰度元素为 32S,氧的天然丰度元素为 16O,碳的天然丰度元素为 12C等。“非同位素富集”化合物是其中化合物中的所有原子或元素都是天然丰度的同位素的化合物,即所有原子或元素的原子质量是在自然界中最丰富。
本申请所公开的稠环酚类化合物,或其药学上可接受的盐或酯,对于PPK1和PPK2之一或者两者具有有很好的抑制作用,用于制备治疗、抑制或预防细菌感染的药物。其中,细菌感染包括PPK相关的细菌感染,可以是PPK1相关的细菌感染,也可以是PPK2相关的细菌感染,或者同时与PPK1和PPK2相关的细菌感染。术语“PPK相关的细菌感染”和“由PPK介导的细菌感染”可互换使用来表示用可受益于PPK抑制剂治疗的任何细菌感染、疾病、失调或病症。
本申请所涉及的PPK相关的细菌感染涵盖那些至少带有PPK中的一种或多种的细菌/病原体所导致的感染。术语“感染”或“细菌感染”包括在对象中或对象上存在细菌,其中如果抑制了该细菌的生长,将会对该对象有益。因此,术语“感染”或“细菌感染”除了涉及细菌的存在之外,还涉及不期望的正常菌群。术语“感染”包括由细菌所引用的感染。这种细菌感染的实例包括许多重点细菌病原体,如绿脓杆菌(P.Aeruginosa)、肺炎克雷伯菌(K.Pneumoniae)、鲍曼不动杆菌(Acinetobacter baumannii)、图拉伦斯氏菌(Francisella tularensis)、空肠杆菌(Campylobacter jejuni)都拥有至少一种PPK1和PPK2。其中绿脓杆菌的基因组中不仅能够编码三种PPK2酶,即PPK2A(PA14_01730)、PPK2B(PA14_33240)和PPK2C(PA14_19410),还能够编码PPK1(PA14_69230)。因此,在一些实施方式中,细菌感染可以是绿脓杆菌引起的感染,也可以是由肺炎克雷伯菌、大肠杆菌、金黄葡萄球菌、沙门氏菌、枯草芽孢杆菌、鲍曼不动杆菌、阴沟肠杆菌、耐万古霉素的肠球菌或耐甲氧西林的金葡菌引起的感染。
其中,术语“生长”是指一种或多种微生物的生长,并且包括微生物(诸 如细菌)的繁殖或种群扩展。该术语还包括维持微生物持续的代谢过程,包括保持微生物存活的过程。
本发明提供的稠环酚类化合物可用作PPK抑制剂,该PPK抑制剂可以同时抑制PPK1和PPK2,也可抑制两者之一。本发明所述的稠环酚类化合物起到抑制PPK活性和/或抗炎活性的作用,并且当需要这种抑制时用作治疗剂或预防性治疗剂。除非另有说明,否则在本文描述本发明化合物的用途时,应当理解的是,这些化合物可为组合物(即,药物组合物)的形式。如本文所使用的,术语“PPK抑制剂”、“PPK阻断剂”、“多磷酸激酶抑制剂”、“多聚磷酸激酶抑制剂”和所有其他相关领域的可接受的术语可互换使用来表示在体外测试、体内模型中和/或表示PPK抑制和潜在治疗或预防疗效的其他测试中能够直接或间接地抑制PPK受体的化合物。该术语也指在人类受试者中呈现出至少一些治疗或预防益处的化合物。
本发明还提供了一种用于治疗、抑制或预防细菌感染,尤其是与PPK相关的细菌感染的抑菌剂/药物,包括上述化合物中的一种或多种,其中细菌感染包括由绿脓杆菌、肺炎克雷伯菌、大肠杆菌、金黄葡萄球菌、沙门氏菌、鲍曼不动杆菌、枯草芽孢杆菌、阴沟肠杆菌或肠球菌引起的感染。术语“抑菌剂”是指能够抑制、降低或阻止细菌生长,抑制或降低细菌在对象中产生感染的能力,或者抑制或降低细菌在环境中繁殖或保持感染的能力,或者降低细菌的感染性或毒力的任何物质、化合物或它们的组合。
本发明提供了药物组合物,该药物组合物包括:本发明所披露的化合物或其药学上可接受的盐或酯,以及药学上可接受的载体。在一些实施方式中,提供了一种药物组合物,该药物组合物包括化合物1至化合物10中的至少一种或其药学上可接受的盐或酯,以及药学上可接受的载体。
在其它实施方式中,本发明提供了用至少一种本发明所提供的PPK抑制剂化合物或组合物来治疗和/或预防免疫相关的疾病、失调和病症,具有 炎性成分的疾病,以及与上述相关的失调的方法。
通过抑制PPK活性可全部或部分治疗或预防的其它疾病、失调和病症,也是本发明提供的PPK抑制剂化合物和组合物的候选适应症。
术语“治疗”是指在已经诊断、观察到了疾病、失调或病症或者其症状之后,开始进行行动(例如施用PPK抑制剂或包含其的药物组合物),以便暂时或永久地消除、减轻、抑制、减缓或改善折磨受试者的疾病、失调或病症的至少一种潜在原因,或者折磨受试者的疾病、失调、病症有关的症状。因此,治疗包括抑制(例如阻止或缓解疾病、失调或病症或与其相关的临床症状的发展或进一步发展)活动性疾病。具体地,如本文中所使用的术语“治疗”用于具体表示将包括根据本发明的化合物或组合物的治疗物给药至已患有感染的患者。术语“治疗”还涉及将根据本发明的化合物或组合物,可选地与一种或多种抗菌剂一起施用以:减轻或缓解细菌感染或与细菌感染相关的一种或多种症状;或者减缓细菌感染或与细菌感染相关的一种或多种症状的发展;或者减轻细菌感染的严重性或与细菌感染相关的一种或多种症状的严重性;或者抑制细菌感染的临床表现;或者抑制细菌感染的不良症状的表现。
术语“预防”是指以某种方式(例如在疾病、失调、病症或其症状发作之前)开始进行行动(例如施用PPK抑制剂或包含其的药物组合物),从而暂时或永久地预防、抑制、压制或降低受试者患有疾病、失调或病症等的风险(如通过例如缺乏临床症状来确定)或在易患特定疾病、病症或病症的受试者的情况下延迟其发作。在某些情况下,该术语还指减缓疾病、失调或病症的进展或抑制其发展成有害的或其他不希望的状态。具体地,本文中所使用的术语“预防”用于表示施用根据本发明的化合物或组合物以预防细菌引起的感染或预防相关感染和/或疾病的发生。术语“预防”还涵盖通过对易被细菌感染的患者或有被细菌感染风险的患者给药,根据本发明的化 合物或组合物的施用来预防至少一种细菌感染。
在一些实施方式中,本发明进一步提供了本文所述的PPK抑制剂化合物和组合物与一种或多种另外的药剂的组合的用途。该一种或多种另外的药剂可具有一些PPK-调节活性和/或它们可通过不同的作用机制起作用。在一些实施方式中,这样的试剂包含辐射(例如局部放射疗法或全身放射疗法)和/或非药理学性质的其他治疗形式。当使用组合疗法时,PPK抑制剂和一种另外的药剂可以是单一组合物或多种组合物的形式,并且治疗方式可以同时、依次或通过一些其他方案来施用。举例来说,在一些实施方式中,提供了在辐射阶段之后进行化学治疗阶段的实施方式。联合疗法可以具有叠加效应或协同效应。
含有活性成分(例如PPK抑制剂)的药物组合物可以是适于口服使用的形式,例如片剂、胶囊、锭剂、糖锭、水性或油性混悬剂、可分散的粉剂或颗粒剂、乳剂、硬质或软质胶囊,或糖浆、溶液、微珠或酏剂。用于口服使用的药物组合物可以根据本领域已知用于制造药物组合物的任何方法来制备,并且这样的组合物可以含有一种或多种试剂,例如甜味剂、调味剂、着色剂和防腐剂以提供药学上可接受的制剂。片剂、胶囊等通常含有与适用于制造片剂的无毒的药学上可接受的载体或赋形剂混合的活性成分。这些载体或赋形剂可以是例如稀释剂,如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;造粒剂和崩解剂,例如玉米淀粉或海藻酸;粘合剂,例如淀粉,明胶或阿拉伯胶以及润滑剂,例如硬脂酸镁、硬脂酸或滑石粉。
在一些实施方式中,组合物是可注射的制剂。在其它实施方式中,组合物被配制为用于口服施用至受试者。
在一些实施方式中,药物组合物容纳在一次性使用的容器(例如,一次性使用的小瓶、安瓿、注射器或自动注射器),而在其它实施方式中,容纳在多次使用容器(例如,多次使用的小瓶)中。
制剂还可包括载体以保护组合物免于从身体快速降解或消失,诸如控释制剂,包括脂质体、水凝胶和微囊化递送系统。例如,可以使用延时材料,例如单独的甘油单硬脂酸酯或甘油硬脂酸酯,或与蜡组合使用。任何药物递送装置都可用于递送PPK抑制剂,包括植入物(例如可植入泵)和导管系统,缓慢注射泵和装置。所有这些都是本领域技术人员所熟知的。
药物组合物也可以是无菌注射水性或油性悬浮液的形式。该悬浮液可以根据已知技术使用本文提到的那些合适的分散剂或润湿剂和悬浮剂来配制。无菌注射制剂还可以是在无毒肠胃外可接受的稀释剂或溶剂中的无菌注射溶液或悬浮液,例如在1,3-丁二醇中的溶液。可以使用的可接受的稀释剂、溶剂和分散介质包括水、林格氏溶液、等渗氯化钠溶液、Cremophor ELTM(BASF,Parsippany,NJ)或磷酸盐缓冲盐水(PBS)、乙醇多、元醇(例如甘油、丙二醇和液体聚乙二醇)及其合适的混合物。另外,无菌的固定油通常用作溶剂或悬浮介质。为此目的,可以使用任何温和的固定油,包括合成的甘油一酯或甘油二酯。而且,脂肪酸(如油酸)可用于制备注射剂。可以通过包括延迟吸收的试剂(例如,单硬脂酸铝或明胶)来实现特定的可注射制剂的延长吸收。
本发明提供的PPK抑制剂化合物和组合物可以以本领域已知的任何适当方式施用于受试者。合适的给药途径包括但不限于口服;肠胃外,例如肌内、静脉内、皮下(例如注射或植入)、腹腔内、脑池内、关节内、脑内(脑实质内和脑室内;鼻腔;阴道;舌下;眼内;直肠;局部(例如透皮);口腔和吸入。一般通过皮下或肌肉内给药的积存注射法也可用于在限定的时间段内释放本文公开的PPK抑制剂。
本发明还提供了包含PPK抑制剂化合物或组合物的试剂盒。试剂盒通常为容纳各种组分的物理结构的形式,并且可用于例如实施本文提供的方法。例如,试剂盒可以包括本发明公开的一种或多种PPK抑制剂(例如提 供在无菌容器中),其可为适合施用至受试者的药物组合物的形式。PPK抑制剂可以以即用型(例如片剂或胶囊)形式或以需要例如在施用前重构或稀释(例如粉末)的形式提供。当PPK抑制剂为需要使用者被重构或稀释的形式时,该试剂盒还可包括与PPK抑制剂一起包装或者分别包装的稀释剂(例如无菌水)、缓冲液、药学上可接受的赋形剂等。当采用组合疗法时,试剂盒可独立地含有几种治疗剂,或者它们可已经在试剂盒中组合。试剂盒的每个组分可以被封装在单独的容器内,并且所有的各种容器可以在单个包装内。本发明的试剂盒可被设计用于适当地保持容纳在其中的组分所需的条件(例如,冷藏或冷冻)。
为了更好地理解本发明并更清楚地展示出如何实现本发明,现通过示例的方式并参考附图,并阐述了根据本发明的实施方式的特征。
实施例
通过参考以下实施例将更容易理解本发明,所述实施例用于说明本发明,而不应被解释为以任何方式限制本发明的范围。
除非另有定义或上下文另有明确规定,本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义。应当理解,与本文所述类似或等同的任何方法和材料可用于本发明的实践或测试。
材料
化合物1
Figure PCTCN2021136707-appb-000003
以2-溴-3,4,5-三甲氧基苯甲酸(2.67g,9.17mmol)为起始原料,合成化合物1。
1H NMR(DMSO-d 6,500MHz)δppm 6.26(s,1H),6.70(s,1H),6.94(d,J=8.5Hz,1H),7.38(d,J=8.5Hz,1H). 13C NMR(DMSO-d 6,125MHz)δppm100.05,109.13,110.81,114.03,114.97,116.87,123.97,133.32,136.51,144.30,145.00,146.98,150.27,163.77,176.67;m/z(ESI +):380.8,382.8.
化合物2
Figure PCTCN2021136707-appb-000004
向没食子酸(10g,5.9mmol)的浓缩悬浮液加入H 2SO 4(80mL)和H 2O(33mL),冷却至-50℃,然后加入K 2S 2O 8(20g,7.4mmol)。在4℃下搅拌16h,过滤沉淀,重结晶得到化合物2(2.0g,10.4%)。
1H NMR(DMSO-d 6,500MHz)δppm 7.49(s,1H); 13C NMR(DMSO-d 6,125MHz)δppm 93.98,108.71,109.51,110.75,113.09,130.92,135.19,136.29,140.02,142.26,146.90,148.68,159.70,162.91;m/z(ESI -):316.8.
化合物3
Figure PCTCN2021136707-appb-000005
将3,4,5-三甲氧基苯甲酸(1g,4.7mmol)、[Rh(NBD)Cl] 2(13.8mg,0.03mmol,0.6mol%)和MnO 2(1.23g,14.1mmol,3equiv)溶于蒸馏水(5mL),在密封管中于150℃下搅拌72h。反应混合物冷却至室温,用2M HCl酸化至pH<3,并浓缩。通过柱层析(MeOH/DCM=1/20~1/5)纯化,得到4,4',5,5',6,6'-六偏甲氧基-[1,1'-联苯]-2,2'-二羧酸(702mg,35.3%)。于0℃和氮气气氛下,将BBr 3(2mL,21.5mmol)滴加到4,4',5,5',6,6'-六甲氧基-[1,1'-联苯]-2,2’-二羧酸(108mg,0.25mmol)在DCM(25mL)的溶液中。将混合物温度慢慢升至室温,再于室温下再搅拌40小时。然后将混 合物慢慢倒入冰中,固体以过滤收集,并用冷甲醇清洗涤。所得固体在真空中干燥,得到化合物3(75mg,99.3%)。
1H NMR(DMSO-d 6,500Hz),δppm 7.46(s,2H),10.55(s,2H),10.80(s,2H); 13C NMR(DMSO-d 6,125Hz),δppm 107.71,110.22,112.34,136.53,139.47,148.11,159.20;m/z(ESI -)301.1.
化合物4
Figure PCTCN2021136707-appb-000006
将ZnO(81.4mg,1.0mmol)加入邻苯二甲酸酐(1.5g,10mmol)和邻苯三酚(2.5g,20mmol)的混合物中,加热至160℃并在该温度下保持2小时,然后冷却至室温。将混合物溶解在1N NaOH(10mL)中并过滤。滤液酸化至pH=7,过滤收集固体物。所得固体用MeOH重结晶,干燥后得到化合物4(2.2g,61.1%)。
1H NMR(CD3OD,500MHz)δppm 6.09(d,J=8.0Hz,2H),6.56(d,J=8.5Hz,2H),7.22(d,J=7.5Hz,1H),7.68(t,J=7.0Hz,1H),7.75(t,J=7.5Hz,1H),7.97(d,J=7.5Hz,1H); 13C NMR(CD3OD,125MHz)δppm 111.12,111.62,117.52,124.14,124.43,126.82,129.58,132.63,134.89,140.70,146.89,170.10;m/z(ESI +):365.3.
化合物5
Figure PCTCN2021136707-appb-000007
以3H-苯并[c][1,2]恶硫醇-3-1,1-二氧化二醇为起始原料,按照化合物4的方法,得到化合物5。
1H NMR(CD3OD,500MHz)δppm 7.17-7.22(m,4H),7.41(d,J=7.5Hz, 1H),7.74(t,J=8.0Hz,1H),7.83(t,J=8.0Hz,1H),8.24(d,J=7.5Hz,1H).
化合物6
Figure PCTCN2021136707-appb-000008
化合物6是购自上海源叶生物科技有限公司的商业产品。
化合物7
Figure PCTCN2021136707-appb-000009
化合物7是购自上海源叶生物科技有限公司的商业产品。
化合物8
Figure PCTCN2021136707-appb-000010
化合物8是购自百灵威的商业产品。
化合物9
Figure PCTCN2021136707-appb-000011
化合物9是购自Aldrich的商业产品。
化合物10
Figure PCTCN2021136707-appb-000012
如上所示,以噻吩-3-基硼酸为起始原料合成化合物10。
1H NMR(DMSO-d6,500MHz)δppm 5.61(s,1H),6.79(s,1H),6.88(d,J=8.5Hz,1H),6.94(dd,J1=4.5Hz,J2=1Hz,1H),7.21-7.22(m,1H),7.25(d,J=8.5Hz,1H),7.40-7.42(m,1H);13C NMR(DMSO-d6,125MHz)δppm108.03,110.36,113.97,114.78,115.62,116.70,123.14,123.89,124.63,130.12,133.29,135.77,136.21,144.65,145.04,146.90,149.99,164.57,176.32;m/z(ESI +):384.8.
化合物A
Figure PCTCN2021136707-appb-000013
化合物A是购自百灵威的商业产品。
化合物B
该化合物也可以自商业渠道购买,本申请所用化合物根据以下反应合成:
Figure PCTCN2021136707-appb-000014
以2-甲氧基苯-1,3-二醇为起始原料合成该化合物。
1H NMR(DMSO-d6,500MHz)δppm 6.87(d,J=8.7Hz,1H),7.36(d,J=8.5Hz,1H),7.51(d,J=8.7Hz,1H),7.57(d,J=8.6Hz,1H),9.31(s,1H),9.70(s,1H),9.80(s,1H),11.22(s,1H).13C NMR(DMSO-d6,125MHz)δppm 105.45,111.48,112.65,113.09,113.41,124.73,127.20,133.36,139.96, 144.54,147.25,149.59,165.78.m/z(ESI-)258.8.
化合物C
Figure PCTCN2021136707-appb-000015
以6-溴-2,3-二甲氧基苯甲酸为起始原料合成该化合物。
1H NMR(DMSO-d6,500MHz)δppm 3.82(s,3H),3.93(s,3H),6.69(d,J=2.5Hz,1H),6.81(dd,J1=2.5Hz J2=9.0Hz,1H),7.66(d,J=9.0Hz,1H),8.01(d,J=9.0Hz,1H),8.08(d,J=9.0Hz,1H).13C NMR(DMSO-d6,125MHz)δppm 56.76,61.11,102.77,109.79,113.35,113.95,118.01,121.01,124.81,129.35,150.82,151.76,152.56,157.30,159.42.m/z(ESI+)272.8.
化合物D
Figure PCTCN2021136707-appb-000016
以间苯二酚为起始原料合成该化合物。
1H NMR(DMSO-d6,500MHz)δppm 6.56-6.58(m,4H),6.71-6.72(m,2H),7.28-7.30(m,1H),7.70-7.74(m,1H),7.78(m,1H),7.80-7.82(m,1H),8.00-8.02(m,1H).
化合物E
Figure PCTCN2021136707-appb-000017
以1,3-二氧-1,3-二氢异苯并呋喃-5-羧酸为起始原料合成该化合物。
1H NMR(CD3OD,500MHz)δppm 7.17(dd,J1=2.0Hz,J2=9.0Hz,2H),7.34(d,J=2.0Hz,2H),7.47(d,J=9.0Hz,2H),8.04(s,1H),8.45-8.47(m,2H).
化合物F
Figure PCTCN2021136707-appb-000018
化合物F是购自Aldrich的商业产品。
化合物G
Figure PCTCN2021136707-appb-000019
化合物G是购自Aldrich的商业产品。
化合物H
Figure PCTCN2021136707-appb-000020
化合物H是购自TCI的商业产品。
生物学测定
1.抑菌实验
为了评价化合物对PPK的抑制效果,使用试剂盒分别针对PPK1、PPK2A、PPK2B、PPK2C对上述化合物进行测试,测试方法参见Liang Peng et al.&Ning Sun(2020)Discovery and antibacterial study of potential PPK1inhibitors against uropathogenic E.coli,Journal of Enzyme Inhibition and Medicinal Chemistry,35:1,1224-1232。化合物由PPK抑制剂筛选实验所获得的实验结果见表1和表2。表1数据表明,本发明所述化合物具有很好的生物活性。其中,化合物4抑制PPK的实验结果见图1。
表1.上述化合物抑制PPK的IC 50
Figure PCTCN2021136707-appb-000021
表2.部分化合物抑制PPK1和PPK2的IC 50
化合物编号 PPK1 PPK2A PPK2B PPK2C
2 20 N/A 59 N/A
3 20 50 48 N/A
4 17 16 20 165
5 26 24 31 273
B 120 N/A N/A N/A
2.生物膜测试
绿脓杆菌可以在培养基内生成生物膜。分别设置A、B、C、D四组LB液体培养基,其中A组接种野生绿脓杆菌(WT),B组接种PPK1敲除的绿脓杆菌(Δppk1),C组接种同时敲除PPK2A、PPK2B、PPK2C的绿脓杆菌(Δppk2A、Δppk2B、Δppk2C),D组接种同时敲掉PPK1和PPK2A、PPK2B、 PPK2C的绿脓杆菌(Δppk1、Δppk2、AΔppk2B、Δppk2C)。ABCD四组培养基被绿脓杆菌感染后,将每组分为两小组,其中一组加入DMSO(-)做为对照,另一组加100μm的化合物4(+)。将细菌于37℃的环境下培养24小时,培养基内会长出一层生物膜,用570nm可见光对A、B、C、D四组培养基内的生物膜进行分析,结果表明:化合物4对野生绿脓杆菌具有很好的抑制效果,能够减少生物膜的形成;并且,该化合物不仅能够抑制PPK1,而且对PPK2也有很好的抑制效果。具体结果见图2。
3.线虫存活测试
将秀丽隐杆线虫分为A、B、C、D、E五组,然后分别进行造模。其中A、B两组接受野生型(WT)绿脓杆菌的感染,其中A组为DMSO对照组,B组为化合物4治疗组;C、D两组接受敲除所有PPK(ΔpolyP,即Δppk1Δppk2AΔppk2BΔppk2C)的绿脓杆菌的感染,其中C组为DMSO对照组,D组为化合物4治疗组;E组作为对照组接受大肠杆菌(OP50E.coli)的感染。造模后,A、C组持续接受空白溶剂DMSO的治疗,B、D、E组持续接受化合物4的治疗,五组实验环境和条件保持一致,六天后计算五组线虫的存活率,结果详见图3。实验表明,线虫感染野生绿脓杆菌后极易死亡,接受化合物4治疗后,死亡率降低显著,且化合物4的疗效与绿脓杆菌敲除PPK的效果类似。
4.HEK细胞毒性测试
实验通过台盼蓝活力测定法在培养的人胚胎肾细胞(HEK 239T)中评估化合物的细胞毒性,分别对空白溶剂DMSO、化合物B以及化合物4进行测试,测试结果详见图4。结果表明,化合物4在高达100μM的浓度时无细胞毒性(相对存活率接近100%),而化合物B则导致大量细胞死亡(相对存活率约为35%)。
本申请公开的稠环酚类化合物,不仅具有较强的活性,还具有安全性 (很低或无细胞毒性);而且对PPK1和PPK2都能有很好的抑制效果。因此,此类化合物制备用于治疗、抑制或预防与PPK相关的细菌感染药物的可行性。
尽管参照本发明的实施例详细描述了本发明,但提供这些实施例是为了说明而不是限制本发明。根据本发明原理能够得到的其它实施例均属于本发明权利要求所界定的范畴。

Claims (13)

  1. 一种稠环酚类化合物在制备用于治疗、抑制或预防细菌感染的药物中的用途,所述化合物选自以下的一种或多种:
    Figure PCTCN2021136707-appb-100001
    Figure PCTCN2021136707-appb-100002
    或其药学上可接受的盐或酯。
  2. 根据权利要求1所述的用途,其中,所述细菌感染包括由产生一种或多种多磷酸激酶(PPK)的细菌所引起的细菌感染,所述PPK例如包括PPK1和PPK2A、PPK2B、PPK2C。
  3. 根据权利要求1或2所述的用途,其中,所述细菌感染包括由绿脓杆菌、肺炎克雷伯菌、大肠杆菌、金黄葡萄球菌、沙门氏菌、枯草芽孢杆菌、鲍曼不动杆菌、阴沟肠杆菌或肠球菌引起的感染。
  4. 根据权利要求1所述的用途,其中,所述化合物中的C、H、O和S原子各自独立选自天然丰度的原子和同位素丰度富集的原子。
  5. 根据权利要求4所述的用途,其中,所述同位素富集的原子选自碳的 12C、 13C和 14C;选自氢的 1H、 2H和 3H;选自氧的 16O、 17O和 18O;以及选自硫的 32S、 33S和 34S。
  6. 一种用于治疗、抑制或预防细菌感染的药物,其中,包括如权利要求1至5中任一项所限定的化合物中的一种或多种,其中所述细菌感染包括与PPK相关的细菌感染。
  7. 组合物在制备用于治疗、抑制或预防细菌感染的药物中的用途,其中,所述组合物包括一种或多种权利要求1至5中任一项所限定的化合物以及至少一种可药用的载体或稀释剂。
  8. 根据权利要求7所述的用途,其中,所述细菌感染包括由产生一种或多种多磷酸激酶(PPK)的细菌所引起的细菌感染。
  9. 根据权利要求7或8所述的用途,其中,所述细菌感染包括由绿脓杆菌、肺炎克雷伯菌、大肠杆菌、金黄葡萄球菌、沙门氏菌、鲍曼不动杆菌、枯草芽孢杆菌、阴沟肠杆菌或肠球菌引起的感染。
  10. 根据权利要求7所述的用途,其中,所述可药用的载体或稀释剂包括乳膏、乳剂、凝胶、脂质体或纳米颗粒。
  11. 根据权利要求7至10中任一项所述的用途,其中,所述组合物适用于口服施用或者可用于注射施用。
  12. 试剂盒在制备用于治疗、抑制或预防细菌感染的药物中的用途,其中,所述试剂盒包括根据权利要求1至5中任一项所限定的化合物或药学上可接受的盐或酯或者根据权利要求7至11中任一项所限定的组合物;以及稀释剂(例如无菌水)、缓冲液、药学上可接受的赋形剂。
  13. 化合物或组合物或试剂盒在抑制PPK酶产生中的用途,其中所述PPK例如包括PPK1和PPK2A、PPK2B、PPK2C,所述化合物为根据权利要求1至5中任一项所限定的化合物或药学上可接受的盐或酯;所述组合物为根据权利要求7至11中任一项所限定的组合物;所述试剂盒为根据权利要求12所限定的试剂盒。
PCT/CN2021/136707 2020-12-09 2021-12-09 稠环酚类化合物的药学应用 WO2022121977A1 (zh)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US18/266,331 US20240131001A1 (en) 2020-12-09 2021-12-09 Pharmaceutical application of fused ring phenolic compounds
CN202180081162.0A CN116568297A (zh) 2020-12-09 2021-12-09 稠环酚类化合物的药学应用
CA3201759A CA3201759A1 (en) 2020-12-09 2021-12-09 Pharmaceutical application of fused ring phenolic compound
EP21902682.0A EP4260854A1 (en) 2020-12-09 2021-12-09 Pharmaceutical application of fused-ring phenolic compound
AU2021394410A AU2021394410A1 (en) 2020-12-09 2021-12-09 Pharmaceutical application of fused-ring phenolic compound

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202011453853.2A CN114601822A (zh) 2020-12-09 2020-12-09 稠环酚类化合物的药学应用
CN202011453853.2 2020-12-09

Publications (1)

Publication Number Publication Date
WO2022121977A1 true WO2022121977A1 (zh) 2022-06-16

Family

ID=81856384

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/136707 WO2022121977A1 (zh) 2020-12-09 2021-12-09 稠环酚类化合物的药学应用

Country Status (6)

Country Link
US (1) US20240131001A1 (zh)
EP (1) EP4260854A1 (zh)
CN (2) CN114601822A (zh)
AU (1) AU2021394410A1 (zh)
CA (1) CA3201759A1 (zh)
WO (1) WO2022121977A1 (zh)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101060867A (zh) * 2004-11-22 2007-10-24 国立大学法人九州大学 生物膜形成抑制剂和治疗用器具
CN101250175A (zh) * 2008-04-01 2008-08-27 赫玉芳 杨梅素的制备方法、药物制剂及医药新用途
CN103622953A (zh) * 2013-12-06 2014-03-12 天津医科大学 一种治疗肾脏囊肿的药物
CN107261158A (zh) * 2017-06-16 2017-10-20 合肥职业技术学院 石榴鞣花酸和没食子酸包合物及其制备方法、药物制剂和应用

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030211465A1 (en) * 1996-05-10 2003-11-13 Mundschenk David D. Immunokine composition and method
WO2007143880A1 (fr) * 2006-06-09 2007-12-21 Shanghai East Best Biopharmaceutical Enterprises Co., Ltd. Composés pour la prévention et le traitement des infections bactériennes, leur préparation et utilisation
WO2014052836A2 (en) * 2012-09-27 2014-04-03 Dunman Paul M Methods and compositions for treating infection
EP2994142A4 (en) * 2013-05-08 2017-03-29 Colorado Seminary, Which Owns and Operates The University of Denver Antibiotic and anti-parasitic agents that modulate class ii fructose 1,6-bisphosphate aldolase
US20170112877A1 (en) * 2014-06-13 2017-04-27 Alexander L. Huang Non-toxic agent for a broad-spectrum, bactericidal or bacteriostatic treatment of antibiotic-resistant bacteria in animals
WO2018195536A1 (en) * 2017-04-21 2018-10-25 Yu Shen Antibacterial compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101060867A (zh) * 2004-11-22 2007-10-24 国立大学法人九州大学 生物膜形成抑制剂和治疗用器具
CN101250175A (zh) * 2008-04-01 2008-08-27 赫玉芳 杨梅素的制备方法、药物制剂及医药新用途
CN103622953A (zh) * 2013-12-06 2014-03-12 天津医科大学 一种治疗肾脏囊肿的药物
CN107261158A (zh) * 2017-06-16 2017-10-20 合肥职业技术学院 石榴鞣花酸和没食子酸包合物及其制备方法、药物制剂和应用

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
"Polyphosphate kinase is essential for biofilm development, quorum sensing, and virulence of Pseudomonas aeruginosa", PNAS, vol. 97, pages 9636 - 9641
BURDA-GRABOWSKA, M. ET AL.: "Bisphosphonic acids and related compounds as inhibitors of nucleotide-and polyphosphate-processing enzymes: A PPK1 and PPK2 case study", CHEM BIOL DRUG DES. 10.1111/CBDD. 13439
HAN QIHENG, ZHANG CHUNHONG, GONG XUE, YANG MIN, LEE MIN HWI : "Research on Distribution of Ellagic Acid Compounds in Melastoma Plants and Pharmacological Activities Thereof", ZHONGYAOCAI - JOURNAL OF CHINESE MEDICINAL MATERIALS, GUOJIA YIYAO GUANLIJU, CN, vol. 41, no. 12, 31 December 2018 (2018-12-31), CN , pages 2962 - 2967, XP055940967, ISSN: 1001-4454, DOI: 10.13863/j.issn1001-4454.2018.12.049 *
LIANG PENGNING SUN ET AL.: "Discovery and antibacterial study of potential PPK1 inhibitors against uropathogenic E. coli", JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, vol. 35, no. 1, 2020, pages 1224 - 1232
NEVILLE NOLAN, ROBERGE NATHAN, JI XIANG, STEPHEN PREYESH, LU JIASHENG LOUIS, JIA ZONGCHAO: "A Dual-Specificity Inhibitor Targets Polyphosphate Kinase 1 and 2 Enzymes To Attenuate Virulence of Pseudomonas aeruginosa", MBIO, vol. 12, no. 3, 29 June 2021 (2021-06-29), XP055940955, DOI: 10.1128/mBio.00592-21 *
PICCAGLI, L. ; BORGATTI, M. ; NICOLIS, E. ; BIANCHI, N. ; MANCINI, I. ; LAMPRONTI, I. ; VEVALDI, D. ; DALL'ACQUA, F. ; CABRIN: "Virtual screening against nuclear factor @kB (NF-@kB) of a focus library: Identification of bioactive furocoumarin derivatives inhibiting NF-@kB dependent biological functions involved in cystic fibrosis", BIOORGANIC, ELSEVIER, AMSTERDAM, NL, vol. 18, no. 23, 1 December 2010 (2010-12-01), AMSTERDAM, NL, pages 8341 - 8349, XP027546693, ISSN: 0968-0896 *
SARABHAI S., ET AL.: "Ellagic acid derivatives from Terminalia chebula Retz. increase the susceptibility of Pseudomonas aeruginosa to stress by inhibiting polyphosphate kinase", JOURNAL OF APPLIED MICROBIOLOGY, WILEY-BLACKWELL PUBLISHING LTD., GB, vol. 118, no. 4, 3 February 2015 (2015-02-03), GB , pages 817 - 825, XP055940979, ISSN: 1364-5072, DOI: 10.1111/jam.12733 *

Also Published As

Publication number Publication date
AU2021394410A9 (en) 2024-05-30
US20240131001A1 (en) 2024-04-25
CA3201759A1 (en) 2022-06-16
EP4260854A1 (en) 2023-10-18
AU2021394410A1 (en) 2023-07-06
CN114601822A (zh) 2022-06-10
CN116568297A (zh) 2023-08-08

Similar Documents

Publication Publication Date Title
EP3445756B1 (en) Compounds and compositions for treating conditions associated with nlrp activity
US10765660B2 (en) Agent containing flavonoid derivatives for treating cancer and inflammation
RU2609259C2 (ru) Пиримидиновые ингибиторы гиразы и топоизомеразы iv
US7074826B2 (en) R-NSAID esters and their use
US20150031663A1 (en) Phthalanilate compounds and methods of use
WO2022121977A1 (zh) 稠环酚类化合物的药学应用
CN101679416B (zh) 1-环丙基-6-氟代-7-(8-甲氧基亚氨基-2,6-二氮杂-螺环[3,4]辛-6-基)-4-氧代-1,4-二氢-[1,8]萘啶-3-羧酸的天冬氨酸盐、其制备方法、以及包含其的抗微生物药物组合物
US20210206706A1 (en) Novel Biphenyl Derivative Compound and Use Thereof
HUE033310T2 (en) Anti-shock agents containing a diamin trifluoromethylpyridine derivative
LU101639B1 (en) Application of Ilexgenin O in preparation of medicament for preventing and treating senile dementia
LU101523B1 (en) Application of taraxasterone in a preparation of medicament for preventing and treating senile dementia
CN110215445B (zh) 香草酸在抑制多重耐药霍氏肠杆菌生长中的应用
JP2023504887A (ja) サルモネラ菌iii型分泌系阻害剤の製造におけるミリセチンの使用
CN113425720A (zh) 亚胺糖化合物在制备抗SARS-CoV-2病毒的药物中的用途
BR122023026497A2 (pt) Uso de um composto e método para produzir um composto
CN110981888A (zh) N-芳基二硫吡咯酮脲类和氨基酯类衍生物及其制备和应用
CN113214097A (zh) 治疗阿尔茨海默病的化合物
CN109121411B (zh) 嘧啶并-异喹啉-醌衍生的化合物、含有它们的药物组合物和它们在细菌性疾病治疗中的用途
US11897859B1 (en) Coumarin compounds as antibacterial agents
JP7360229B2 (ja) フェロトーシス阻害剤及びその用途
US11958853B1 (en) 6-substituted aminopyrazino[2′,1′:2,3]imidazo[4,5-c][1,7]naphthyridine compounds as CK2 inhibitors
US10954262B2 (en) Tunicamycin analogues
US20210052537A1 (en) Colitis ameliorating agent
CN111606900A (zh) 一种抗感染药物及其制备方法和应用
BR112021011875B1 (pt) Composto e composição farmacêutica

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21902682

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 202180081162.0

Country of ref document: CN

ENP Entry into the national phase

Ref document number: 3201759

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 18266331

Country of ref document: US

ENP Entry into the national phase

Ref document number: 2021394410

Country of ref document: AU

Date of ref document: 20211209

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2021902682

Country of ref document: EP

Effective date: 20230710