WO2007143880A1 - Composés pour la prévention et le traitement des infections bactériennes, leur préparation et utilisation - Google Patents

Composés pour la prévention et le traitement des infections bactériennes, leur préparation et utilisation Download PDF

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Publication number
WO2007143880A1
WO2007143880A1 PCT/CN2006/001267 CN2006001267W WO2007143880A1 WO 2007143880 A1 WO2007143880 A1 WO 2007143880A1 CN 2006001267 W CN2006001267 W CN 2006001267W WO 2007143880 A1 WO2007143880 A1 WO 2007143880A1
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Prior art keywords
compound
pharmaceutically acceptable
bacterial infection
antibiotics
disease
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PCT/CN2006/001267
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English (en)
Chinese (zh)
Inventor
Mingwei Wang
Jianshu Xie
Dexu Zhu
Mitsumi Muramatsu
Lei Tang
Bojun Li
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Shanghai East Best Biopharmaceutical Enterprises Co., Ltd.
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Application filed by Shanghai East Best Biopharmaceutical Enterprises Co., Ltd. filed Critical Shanghai East Best Biopharmaceutical Enterprises Co., Ltd.
Priority to PCT/CN2006/001267 priority Critical patent/WO2007143880A1/fr
Publication of WO2007143880A1 publication Critical patent/WO2007143880A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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

Definitions

  • the present invention relates to the treatment or prevention of infection by certain bacteria, in particular methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and extended-spectrum ⁇ -lactamase (ESBLs)
  • MRSA methicillin-resistant Staphylococcus aureus
  • MRSE methicillin-resistant Staphylococcus epidermidis
  • ESBLs extended-spectrum ⁇ -lactamase
  • MRSA methicillin-resistant Staphylococcus aureus
  • PRSP penicillin-resistant Streptococcus pneumoniae
  • VRE vancomycin-resistant enterococci
  • MDRMT multi-drug resistant tuberculosis
  • the emergence of bacterial resistance is the result of the complex interaction between microorganisms and the environment and antibiotics. According to its pathogenesis, it is divided into two types: environmental mediation and self-mediated.
  • the main mechanisms for obtaining drug resistance due to bacterial mutations caused by exposure to drugs include: (1) production of specific antibiotic inactivating enzymes; (2) mutation of the target site and no response to drugs; (3) changes in outer membrane permeability , block the entry of drugs; (4) enhance the efflux, accelerate the pumping of drugs into the bacteria.
  • the MRSA strain in S. aureus was 5% before 1980 and 24% between 1985 and 1986, and after 1990 it was resistant to methicillin-resistant coagulase-resistant Staphylococcus (MRCNS) accounted for 50-70% of the total number of Staphylococcus aureus and Staphylococcus, and the incidence of other resistant bacteria also showed an upward trend.
  • MRCNS methicillin-resistant coagulase-resistant Staphylococcus
  • antibacterial drugs against bacterial DNA replication can also block the spread of drug-resistant genetic traits, and thus become a research hotspot for the treatment of drug-resistant bacterial infections.
  • Japanese scientist Kato et al. found that a trypsin-like proteinase is involved in the initial stage of E. coli DNA replication and named it Protease In c.
  • Proteinase In is widely present in various bacteria. , encoded by the PrlC gene, has two active centers of tryptase and oligopeptidase, which play a key role in the initial stage of DNA replication.
  • Biochemical and genetic studies have shown that most bacteria have similar reproductive mechanisms, and compounds that specifically block DNA replication are likely to have a broad spectrum of antibacterial effects.
  • the new antibiotics that block the initial replication of bacterial DNA not only have the effect of inhibiting bacterial growth but also the inheritance of drug resistance traits, and their bursting potential is enormous.
  • the present invention starts from the initiation of blocking bacterial DNA replication, and synthesizes a series of compounds containing a thiol group and a biphenyl group through rational drug design. Experiments have shown that such compounds are useful for a variety of bacteria such as methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, extended-spectrum ⁇ -lactamase-producing Escherichia coli, and Klebsiella pneumoniae. The inactivated Enterococcus faecalis has strong antibacterial activity.
  • the invention provides related technologies and applications for synthesizing a new class of high-efficiency, broad-spectrum and low-toxic antibiotics. Purpose of the invention
  • Another object of the invention is to provide a process for the preparation of a compound of formula I;
  • Another object of the invention is to provide a pharmaceutical composition comprising a compound of formula I;
  • Another object of the invention is to provide the use of a compound of formula I for the manufacture of a medicament for the treatment of bacterial infectious diseases.
  • the present invention provides inhibitors that prevent the initiation of replication of certain bacterial DNA, adding members of the antibiotic.
  • the present invention relates to a compound of the formula I, or a pharmaceutically acceptable salt thereof:
  • n is an integer from 0 to 1
  • R is selected from hydrogen, d- 6 alkyl or C 6 -12 aryl and halogen
  • X is selected from oxygen or nitrogen
  • Y is unselected or selected from keto or nitrogen.
  • the compound has the following formula:
  • the compound or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical composition, either alone or in combination with a pharmaceutically acceptable carrier or excipient.
  • the invention also provides a kit comprising the above compound for treating or preventing infection by bacteria, such as methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, Escherichia coli and Klebsiella pneumoniae producing extended-spectrum ⁇ -lactamases, and Enterococcus faecalis infections produced by inactivating enzymes Disease or symptom.
  • the invention in another aspect, relates to a method of treating or preventing a disease or condition caused or accompanied by a bacterial infection.
  • the method comprises administering to a subject in need or willingness to treat or prevent, an effective amount of a compound which selectively inhibits the initiation of bacterial DNA replication, or a pharmaceutically acceptable salt thereof, for treating or preventing the above-mentioned diseases or symptoms.
  • the above diseases or symptoms are caused by methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, extended-spectrum ⁇ -lactamase-producing Escherichia coli and Klebsiella pneumoniae, and blunt The enzyme caused by Enterococcus faecalis infection caused or accompanied.
  • bacteria in particular methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, extended-spectrum ⁇ -lactamase-producing Escherichia coli and Klebsiella pneumoniae and An enterococcus faecal infection producing a passivation enzyme, the disease or symptom caused or accompanied by treatment or prevention by administering an effective amount of a compound of the formula I or a pharmaceutically acceptable salt thereof:
  • the present invention relates to a combination preparation comprising a methicillin-resistant epidermis which selectively inhibits bacterial growth, particularly methicillin-resistant Staphylococcus aureus Staphylococcus, Escherichia coli and Klebsiella pneumoniae producing extended-spectrum ⁇ -lactamase, and a compound which initiates replication of Enterococcus faecalis DNA producing a passivation enzyme, or a pharmaceutically acceptable salt thereof, and A pharmaceutically acceptable carrier or excipient.
  • the combination formulation comprises a compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. This compound has the following formula I:
  • n is an integer from 0 to 1
  • R is selected from hydrogen, alkyl or C 6 .12 aryl and halogen
  • X is selected from oxygen or nitrogen
  • Y is not selected or selected from keto or nitrogen.
  • the compound has the following formula:
  • the present invention also provides a kit comprising the above combined preparation.
  • the present invention still further provides the use of the above-mentioned combination preparation for treating or preventing infection by bacteria, such as methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, and extended-spectrum ⁇ -lactamase-producing Escherichia coli.
  • bacteria such as methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, and extended-spectrum ⁇ -lactamase-producing Escherichia coli.
  • methicillin-resistant Staphylococcus aureus refers to a strain of Staphylococcus aureus that is resistant to methicillin.
  • methicillin-resistant Staphylococcus epidermidis refers to a strain of Staphylococcus epidermidis that is resistant to methicillin.
  • Escherichia coli producing extended-spectrum ⁇ -lactamase refers to a class of Escherichia coli, under the selective pressure of antibiotics, penicillins, first, second, third generation cephalosporins and ammonia in vitro. Qunan shrinks its antibacterial ring, but it is not necessarily in the range of drug resistance. Adding enzyme inhibitors such as clavulanic acid, sulbactam and tazobactam can enlarge the inhibitory ring. It is resistant to ⁇ -lactams (including penicillins and cephalosporins) in clinical treatment, but sensitive to carbapenems and cephalosporins. Mediated by plasmids, often mutated from the common ⁇ -lactamase gene (TEM-1, TEM-2, SHV-1).
  • TEM-1, TEM-2, SHV-1 common ⁇ -lactamase gene
  • extra-broad-spectrum ⁇ -lactamase-producing Klebsiella pneumoniae refers to a class of Klebsiella, penicillins, first, second, third-generation cephalosporins in vitro, under the selective pressure of antibiotics.
  • Aztreonam reduces its inhibitory ring, but it is not necessarily in the range of drug resistance.
  • Adding clavulanic acid, sulbactam and tazobactam to inhibit the inhibitory ring. It is resistant to ⁇ -lactams (including penicillins and cephalosporins) in clinical treatment, but sensitive to carbapenems and cephalosporins. It is mediated by plasmids and is often mutated from the common ⁇ -lactamase gene (TEM-1, TEM-2, SHV-1).
  • Enterococcus faecalis producing a passivating enzyme refers to a type of Enterococcus faecalis producing an aminoglycoside inactivating enzyme, which is inactivated by modification of an aminoglycoside antibiotic by an aminoglycoside inactivating enzyme.
  • Highly resistant to this class of antibiotics eg gentamicin, streptomycin, kanamycin, paromomycin and tobramycin
  • a disease or condition caused or associated with methicillin-resistant Staphylococcus aureus infection refers to diseases and symptoms caused by methicillin-resistant Staphylococcus aureus infection alone, or by hereditary and/or Other factors and conditions of acquiredness are caused together.
  • a disease or condition caused or associated with infection with methicillin-resistant Staphylococcus epidermidis refers to diseases and symptoms caused by methicillin-resistant Staphylococcus epidermidis infection alone, or by hereditary and/or acquired Other factors and conditions are caused together.
  • a disease or condition caused or associated with Escherichia coli infection by an extended spectrum beta-lactamase refers to a disease caused by Escherichia coli infection of an extended spectrum beta-lactamase. And symptoms, or caused by other factors and conditions of hereditary and / or acquired.
  • a disease or condition caused or associated with Klebsiella pneumoniae infection by an extended-spectrum ⁇ -lactamase refers to a single infection caused by Klebsiella pneumoniae producing an extended-spectrum ⁇ -lactamase. Diseases and symptoms, or caused by other factors and conditions of hereditary and / or acquired.
  • a disease or condition caused or accompanied by infection with Enterococcus faecalis producing a passivating enzyme refers to a disease caused by Enterococcus faecalis that produces a passivating enzyme, a disease or symptom caused by it alone, or obtained by heredity and/or Other factors and conditions of sexuality are caused together.
  • an "effective amount" of a compound for treating a particular condition refers to an amount sufficient to ameliorate or to some extent alleviate the symptoms associated with the disease.
  • This dose can be administered in a single dose or in accordance with a therapeutic regimen. This dose cures the disease, but is typically administered to improve the condition. Repeated administration to improve symptoms may be desirable.
  • pharmaceutically acceptable salts, esters or other derivatives include any salt, ester or derivative which is readily prepared by those skilled in the art by known methods.
  • the compounds thus derived and produced can be administered to animals and humans without toxic effects.
  • the compound is either pharmaceutically active or a prodrug.
  • treatment means that the disease and condition are improved in any way, or other beneficial changes. Treatment also includes the use of the compounds of the invention in medicine.
  • administration of a particular pharmaceutical composition to "improve" the symptoms of a particular disease means any reduction, whether permanent, temporary, prolonged, transient, can be attributed to or associated with the pharmaceutical composition. Relevant application.
  • substantially pure means sufficient homogeny to detect impurities by standard analytical methods used by those skilled in the art to evaluate purity, such as thin layer chromatography.
  • substantially chemically pure compounds for purification are well known to those skilled in the art.
  • a substantially chemically pure compound may be a stereoisomer or a mixture of isomers. In this case, further purification may increase the specific activity of the compound.
  • prodrug refers to a compound administered in vivo that can be metabolized or converted to a biologically, pharmaceutically or therapeutically active form.
  • the pharmaceutically active compound will be modified to reproduce the active compound by metabolic processes.
  • Prodrug Precursors that can be designed to alter their metabolic stability, or transport properties, to mask their side effects or toxicity, to improve the taste of the drug, or to alter other properties.
  • substantially is the same or uniform or similar, and the understanding of the relevant art by those skilled in the art may vary in the context, and is generally at least 70%, preferably at least 80%, more preferably at least 90%, most Excellent at least 95% identical.
  • composition refers to any mixture. It can be a solution, suspension, liquid, powder, ointment, aqueous, non-aqueous or any combination thereof.
  • object as used herein includes humans and animals, for example, dogs, cats, cows, pigs, rodents, and the like.
  • bacteria such as methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, and extended-spectrum ⁇ -lactamase producing large intestine
  • Escherichia coli and Klebsiella pneumoniae and Enterococcus faecalis infections that produce inactivating enzymes, diseases or symptoms caused or accompanied.
  • the present invention is added to the antibiotic series by providing a drug which inhibits the initiation of DNA replication by certain bacteria.
  • One aspect of the invention relates to a compound of formula I, or a pharmaceutically acceptable salt thereof:
  • n is an integer of 0-1, R is selected from hydrogen, C 12 _ 6 alkyl or aryl group, and halogen; X is selected oxygen or nitrogen; or the Y is not selected from the group selected from a ketone or nitrogen.
  • the thiol group can be any suitable aliphatic group, including anthracene, alkene, alkyne, and a cycloaliphatic group; it can also be a linear hydrocarbon group, or include a suitable substituent such as a halide.
  • the lower aryl group may be a straight hydrocarbon group or may include a suitable substituent such as a halide.
  • the compound has the following formula II:
  • R group preferably contains any aryl or ester.
  • the compounds of the present invention may be a specific stereoisomer, such as the R- or S-configuration, or a mixture thereof, for example, a racemic mixture.
  • the compounds contemplated herein include all classes of compounds having pharmaceutical activity, or solutions or mixtures thereof. Also included are hydration types such as aqueous solutions, hydrolysates or ionized products of these compounds; and these compounds may contain varying amounts of bound water molecules.
  • the compounds of the invention may be prepared or synthesized according to any suitable method.
  • the compound is prepared by the synthetic procedure cited in Section F below.
  • the compound or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical composition, either alone or in combination with a pharmaceutically acceptable carrier or excipient.
  • the compounds of the invention may be prepared in the form of their pharmaceutically acceptable salts with any suitable acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like can be used. Its In his case, organic acids such as formic acid, acetic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid and the like can be used.
  • a mercaptosulfonic acid such as methanesulfonic acid, ethylsulfonic acid or the like can be used.
  • an arylsulfonic acid such as benzenesulfonic acid, p-toluenesulfonic acid or the like can be used.
  • the present invention relates to the treatment and prevention of bacterial infections, in particular, methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, extended-spectrum ⁇ -lactamase-producing Escherichia coli and pneumonia
  • a method for the infection or infection of a bacterium caused by Enterococcus faecalis with a passivating enzyme comprising administering an effective amount of a selective inhibition of bacterial DNA replication initiation to a subject in need or willing to receive treatment or prevention.
  • An agent, or a pharmaceutically acceptable salt is used to prevent or prevent the above diseases and conditions.
  • the above diseases and symptoms are caused by methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, extended-spectrum ⁇ -lactamase-producing Escherichia coli and Klebsiella pneumoniae, and Inactivated Enterococcus faecalis caused or accompanied.
  • the above-mentioned diseases or symptoms caused by bacteria are treated or prevented by administering to the subject an effective amount of a compound of the formula I or a pharmaceutically acceptable salt thereof:
  • n is an integer from 0 to 1
  • R is selected from hydrogen, d- 6 alkyl or C 6 -12 aryl and halogen
  • X is selected from oxygen or nitrogen
  • Y is unselected or selected from keto or nitrogen.
  • Any suitable compound or pharmaceutically acceptable salt thereof may be used, including those described in Section B above.
  • the compound administered has the following formula: Oo
  • Any subject preferably a mammal, more preferably a human, can be treated by this method.
  • the method can be used to control any methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, extended-spectrum ⁇ -lactamase-producing Escherichia coli and Klebsiella pneumoniae and passivation Enzymes caused by diseases and symptoms caused by Enterococcus faecalis infection.
  • Preferred diseases are various acute and chronic respiratory infections, urinary tract infections, biliary infections, gynecological infections, epidermal and soft tissue infections, ENT and dental infections.
  • the compounds of the present invention may be used alone or in combination with other antibiotics already on the market or to be marketed. Any suitable antibiotic can be used in combination with the compounds of the present invention.
  • Typical antibiotics include penicillin and its derivatives, cephalosporins and their derivatives, macrolide antibiotics, aminoglycoside antibiotics, tetracycline antibiotics, neoglycopeptide antibiotics, peptide antibiotics, new quinolone antibiotics, evil An oxazolidinone antibiotic, a dihydrofolate reductase inhibitor, and various antibiotic enhancers.
  • the above antibiotics are not administered when the compounds of the invention are used. More preferably, the compounds of the present invention are used to treat or prevent diseases and symptoms caused by drug-resistant strains induced by the above-mentioned antibiotics.
  • the compounds of the invention may be administered alone or in combination with other suitable antibiotics by any suitable method.
  • it can be administered by intraluminal injection, subcutaneous injection, intravenous injection, intramuscular injection, intradermal injection, orally or topically with a compound of the present invention, or with a pharmaceutically acceptable salt thereof.
  • the method further comprises performing a diagnostic and prognostic assessment of the bacterial infection of the subject.
  • Any suitable method can be used to diagnose and assess the prognosis of a bacterial infection.
  • Diagnosis and prognosis can be based on detecting and/or identifying any or all bacterial proteins, such as its enzymes, antigens, antibodies, nucleic acids or other pathological and clinical markers as well as symptoms.
  • the diagnostic or prognostic methods disclosed in the international patents WO 01/44815 and U.S. Patent 5,571,674 can be used.
  • the invention also relates to a combination formulation comprising a compound which selectively inhibits the initial replication of DNA of said bacterium, or a pharmaceutically acceptable salt thereof, and one or more antibiotics.
  • such a combination comprises a compound or a pharmaceutically acceptable salt thereof and one or A variety of antibiotics, the compound has the following formula I:
  • n is an integer from 0 to 1
  • R is selected from hydrogen, d- 6 alkyl or 12 aryl and halogen
  • X is selected from oxygen or nitrogen
  • ⁇ is not selected or selected from keto or nitrogen. More preferably, the compound included in the combined preparation has the following formula:
  • any suitable antibiotic can be used in the combination formulation of the invention.
  • one or more of the above antibiotics may be included in the combination formulation of the invention.
  • a method of treating or preventing infection by bacteria such as methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, and extended-spectrum ⁇ -lactamase-producing large intestine
  • bacteria such as methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, and extended-spectrum ⁇ -lactamase-producing large intestine
  • a method of infection with Escherichia coli and Klebsiella pneumoniae and Enterococcus faecalis producing a passivating enzyme, a disease or symptom caused or accompanied by a method comprising administering an effective amount of the above-mentioned combined preparation to a subject in need thereof and willing to treat or prevent it Or a pharmaceutically acceptable salt thereof, thereby treating or preventing the above diseases or symptoms.
  • kits comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, and the use of the above compound or a pharmaceutically acceptable salt thereof for controlling a bacterial infection, such as nail resistance Oxidant-induced Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, Escherichia coli producing Klebsiella pneumoniae and extended-infection of Enterococcus faecalis Instructions for the use of the disease or symptom.
  • a bacterial infection such as nail resistance Oxidant-induced Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, Escherichia coli producing Klebsiella pneumoniae and extended-infection of Enterococcus faecalis Instructions for the use of the disease or symptom.
  • kits including the above-described combined preparation and use of the combination Formulations for the treatment or prevention of bacterial infections, such as methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, extended-spectrum ⁇ -lactamase-producing Escherichia coli and Klebsiella pneumoniae Instructions for the use of inactivated Enterococcus faecalis infections, diseases or symptoms caused.
  • bacterial infections such as methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, extended-spectrum ⁇ -lactamase-producing Escherichia coli and Klebsiella pneumoniae
  • the compounds of the invention are formulated for any suitable route of administration, for example, intraluminal, subcutaneous, intravenous, intramuscular, intradermal Injection, oral or topical.
  • the method can be administered by injection, in a single dose, in an ampoule, or in a multi-dose container with an additional buffer.
  • the formulations may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles.
  • the formulations may contain formulating agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in the form of a powder in the form of a suitable carrier, sterile non-pyrogenic water or other solvent.
  • the topical medicament of the present invention may be a foam, a gel, an ointment, an ointment, a transdermal patch, or a paste.
  • compositions and methods for administration which may be used in the present invention include, but are not limited to, those reported in U.S. Patent Nos. 5,736,154, 6,197,801 Bl, 5,741,511, 5,886,039, 5,941,868, 6,258,374, and 5,686,102.
  • the size of the dose to be treated or prevented will vary depending on the severity of the condition and the route of administration.
  • the frequency of dosing and medication will vary with age, weight, health status, and individual patient response.
  • Dosage forms include tablets, troches, lenticular capsules, dispersing agents, suspending agents, solutions, capsules, films and the like.
  • the compound of the present invention may be in accordance with a general pharmaceutical mixing technique with a pharmaceutical carrier or excipient such as a cyclodextrin and 2-hydroxy-propyl- ⁇ -cyclodextrin. Tightly mixed.
  • a pharmaceutical carrier or excipient such as a cyclodextrin and 2-hydroxy-propyl- ⁇ -cyclodextrin. Tightly mixed.
  • a special carrier a local or parenteral route, may be employed.
  • parenteral dosage forms such as compositions for intravenous injection or infusion
  • similar pharmaceutical vehicles can be employed, water, glycols, oils, buffers, sugars, preservatives, liposomes, etc., which are well known to those skilled in the art. .
  • parenteral compositions include, but are not limited to, 5% w/v dextrose, physiological saline or other solutions.
  • the total dose of the compound of the present invention, alone or in combination with other preparations, can be administered in vial vials in a volume of from about 1 ml to about 2000 ml. According to PT/CN2006/001267 The total dose of the drug, the amount of diluent will also be different.
  • the invention also provides a kit for achieving a therapeutic regimen.
  • the kit comprises an effective amount of a compound of the invention in a pharmaceutically acceptable form, either alone or in combination with other agents, in one or more containers.
  • the preferred pharmaceutical form is in combination with sterile saline, dextrose solution, buffer solution, or other pharmaceutically acceptable sterile liquid.
  • the composition may be lyophilized or dried; in this case, the kit optionally further comprises a pharmaceutically acceptable solution, preferably a sterile solution, in a container to reconstitute the complex A solution for injection purposes is formed.
  • Typical pharmaceutically acceptable solutions are saline solutions and dextrose solutions.
  • the kit of the present invention further comprises a needle or syringe and/or a packaged alcohol pad for injection of the composition, preferably in sterile form. Instructions for use by a doctor or patient may optionally be included.
  • the present invention meets this need, and through systematic research and in vitro activity screening, it is found that the compounds covered by the present invention can efficiently and selectively inhibit the growth of a variety of clinically resistant bacteria, thereby developing new antibiotics and developing higher titers. Multi-drug combination therapy paved the way. N2006/001267
  • HPllOO HPLC system with binary gradient pump, online vacuum degasser, autosampler, column oven and photodiode array detector.
  • the column is ZORBAX ODS (4.6 x 250 mm), flow 67
  • 4- 4-aminobiphenyl V 4'-indole benzamide hydrochloride Add 1.7 g (0.01 mol) of 4-aminobiphenyl, 2.2 g (0.01 mol) of 4-mercaptobenzoic acid hydrochloride and 4.1 g (0.02 mol) of DCC to 150 ml of pyridine at room temperature. Stir for 48 hours. After the insoluble material was filtered, the filtrate was evaporated to dryness.
  • the compounds EB-1 and EB-2 described here should be 4-(4-biphenyl)-4'-indolyl benzoate hydrochloride and 4-(4-aminobiphenyl), respectively.
  • - 4-Methylbenzamide hydrochloride which specifically inhibits the growth of cocci. Eight synthetic compounds against Staphylococcus aureus standard strain (ATCC25923), Sarcinia septicum standard strain (ATCC9341), Staphylococcus epidermidis standard strain (ATCC12228), Pseudomonas aeruginosa standard strain (ATCC2785), and dysentery bacillus standard strain were tested. The minimum inhibitory concentration (MIC, g/ml) of E.
  • MIC is less than 0.01 mg/ml
  • EB-2 is on the epidermis Staphylococcus including MRSE has an MIC of 0.16 mg/ml
  • EB-2 and EB-7 for Escherichia coli and Klebsiella pneumoniae producing extended-spectrum enzymes (ESBLs), and Enterococcus faecalis producing inactivated enzymes ( Five aminoglycoside antibiotics are highly resistant) and also have strong antibacterial activity (see Table 2).
  • Escherichia coli >0.32 0.16 0.32 >0.08 0.32 >0.16 >0.32 0.03
  • ESBLs-producing Escherichia coli >0.32 0.16 0.32 >0.08 0.32 >0.16 >0.32 0.125 ESBLs pneumonia Kreiber >0.32 0.32 0.32 >0.08 0.16 >0.16 >0.32 S0.03 Bacillus 03-7
  • Pseudomonas aeruginosa >0.32 0.32 0.32 >0.08 >0.32 >0.16 >0.32 0.5

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  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pulmonology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Urology & Nephrology (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de formule structurale générale I ainsi que leurs sels pharmaceutiquement acceptables, dans laquelle n = 0 ou 1; R = H, alkyle en C1-6 ou aryle en C6-12; X = O ou NH; et Y est absent, carbonyle ou NH. Les composés selon l'invention sont préparés à partir de deux composés correspondants par le biais de l'estérification ou de l'amidation. Lesdits composés peuvent être utilisés pour le traitement ou la prévention d'infections bactériennes, en particulier pour des maladies induites par le staphylocoque doré résistant à la méticilline, le Staphylococcus epidermidis résistant à la méticilline, Escherichia coli et Klebsiella aerogenes capables de produire des β-lactamases à superspectre, et Enterococcus faecalis capable de produire une enzyme inactive.
PCT/CN2006/001267 2006-06-09 2006-06-09 Composés pour la prévention et le traitement des infections bactériennes, leur préparation et utilisation WO2007143880A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016108045A3 (fr) * 2014-12-31 2016-09-15 Swansea University Composés antimicrobiens, compositions et méthodes associées
CN106543041A (zh) * 2016-05-22 2017-03-29 上海清松制药有限公司 一种对胍基苯甲酸盐酸盐的合成方法
CN113684144A (zh) * 2021-07-22 2021-11-23 广东药科大学 一株昆虫蜚蠊肠道内生链霉菌wa5-1-7及其应用
CN114601822A (zh) * 2020-12-09 2022-06-10 润佳（苏州）医药科技有限公司 稠环酚类化合物的药学应用

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DE1905813A1 (de) * 1968-07-04 1970-03-05 Akad Wissenschaften Ddr 3- oder 4-Guanidobenzoesaeurebenzyl- oder -phenylestern und deren Verwendung als Inhibitoren
FR2456731A1 (fr) * 1979-05-16 1980-12-12 Choay Sa Nouveaux derives substitues d'ary
EP0222608A2 (fr) * 1985-11-12 1987-05-20 Ono Pharmaceutical Co., Ltd. Dérivés de l'acide p-guanidino-benzoique et compositions pharmaceutiques ayant ces dérivés comme agent actif
CN1410419A (zh) * 2001-09-26 2003-04-16 朱德煦 治疗或预防细菌感染的方法和组合物
CN1810777A (zh) * 2005-01-24 2006-08-02 上海东浩医药生物企业有限公司 一类治疗或预防细菌感染的化合物及其制备方法和用途

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DE1905813A1 (de) * 1968-07-04 1970-03-05 Akad Wissenschaften Ddr 3- oder 4-Guanidobenzoesaeurebenzyl- oder -phenylestern und deren Verwendung als Inhibitoren
FR2456731A1 (fr) * 1979-05-16 1980-12-12 Choay Sa Nouveaux derives substitues d'ary
EP0222608A2 (fr) * 1985-11-12 1987-05-20 Ono Pharmaceutical Co., Ltd. Dérivés de l'acide p-guanidino-benzoique et compositions pharmaceutiques ayant ces dérivés comme agent actif
CN1410419A (zh) * 2001-09-26 2003-04-16 朱德煦 治疗或预防细菌感染的方法和组合物
CN1810777A (zh) * 2005-01-24 2006-08-02 上海东浩医药生物企业有限公司 一类治疗或预防细菌感染的化合物及其制备方法和用途

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016108045A3 (fr) * 2014-12-31 2016-09-15 Swansea University Composés antimicrobiens, compositions et méthodes associées
CN106543041A (zh) * 2016-05-22 2017-03-29 上海清松制药有限公司 一种对胍基苯甲酸盐酸盐的合成方法
CN114601822A (zh) * 2020-12-09 2022-06-10 润佳（苏州）医药科技有限公司 稠环酚类化合物的药学应用
CN113684144A (zh) * 2021-07-22 2021-11-23 广东药科大学 一株昆虫蜚蠊肠道内生链霉菌wa5-1-7及其应用
CN113684144B (zh) * 2021-07-22 2023-01-31 广东药科大学 一株昆虫蜚蠊肠道内生链霉菌wa5-1-7及其应用

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