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US20180042918A1 - Respiratory infection treating agent - Google Patents

Respiratory infection treating agent Download PDF

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Publication number
US20180042918A1
US20180042918A1 US15/554,329 US201615554329A US2018042918A1 US 20180042918 A1 US20180042918 A1 US 20180042918A1 US 201615554329 A US201615554329 A US 201615554329A US 2018042918 A1 US2018042918 A1 US 2018042918A1
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Prior art keywords
treating agent
fluoroethyl
methoxy
oxo
carboxylic acid
Prior art date
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US15/554,329
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English (en)
Inventor
Kota KUME
Hisao Yoshida
Hirotaka ANDO
Yuta Tanaka
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Kyorin Pharmaceutical Co Ltd
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Kyorin Pharmaceutical Co Ltd
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Assigned to KYORIN PHARMACEUTICAL CO., LTD. reassignment KYORIN PHARMACEUTICAL CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ANDO, HIROTAKA, KUME, Kota, TANAKA, YUTA, YOSHIDA, HISAO
Publication of US20180042918A1 publication Critical patent/US20180042918A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/04—Drugs for disorders of the respiratory system for throat 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
    • Y—GENERAL 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
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against 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 a respiratory infection treating agent.
  • quinolone carboxylic acid-based antibacterial agents called new quinolone have been developed worldwide.
  • new quinolone-based antibacterial agents are generally used as an infection treating agent.
  • Patent Literature 1 a quinolone carboxylic acid derivative represented by a general formula (1) is disclosed by this applicant (Patent Literature 1).
  • R 1 is an alkyl group having 1 to 6 carbon atoms of which 1 or 2 or more hydrogen atoms may be substituted with 1 or 2 or more halogen atoms, a cycloalkyl group which has 3 to 6 carbon atoms and may be substituted with 1 or 2 or more halogen atoms, or an aryl or heteroaryl group which may be substituted with 1 or 2 or more substituents which are the same or different and are selected from a halogen atom and an amino group;
  • R 2 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a pharmaceutically acceptable cation;
  • R 3 is a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, or an alkyl group having 1 to 3 carbon atoms;
  • R 4 is a hydrogen atom or a halogen atom;
  • R 5 is a fluorine atom;
  • R 6 is a hydrogen atom or a fluorine
  • Patent Literature 1 also discloses 7-[(3S,4S)-3- ⁇ (cyclopropylamino)methyl ⁇ -4-fluoropyrrolidine-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as one example of the quinolone carboxylic acid derivative.
  • a hydrochloride salt thereof is disclosed in Patent Literature 2.
  • An object of the present invention is to provide a novel respiratory infection treating agent.
  • the present inventor has studied a safer and more effective respiratory infection treating agent.
  • quinolone carboxylic acid derivatives represented by the general formula (1) 7-[(3S,4S)-3- ⁇ (cyclopropylamino)methyl ⁇ -4-fluoropyrrolidine-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and a pharmaceutically acceptable salt thereof, and in particular, a hydrochloride salt thereof have significantly high tissue distribution ratio into the respiratory organ (particularly, the lung) and distribute into the respiratory organ rapidly after administration, and therefore, are extremely useful as a respiratory infection treating agent.
  • the present invention has thus been completed.
  • a respiratory infection treating agent containing, as an active ingredient, 7-[(3S,4S)-3- ⁇ (cyclopropylamino)methyl ⁇ -4-fluoropyrrolidine-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof.
  • pathogenic bacteria causing the respiratory infection are one or two or more types of bacteria selected from the group consisting of bacteria belonging to Staphylococcus sp., bacteria belonging to Streptococcus sp., Moraxella catarrhalis , bacteria belonging to Klebsiella sp., Haemophilus influenzae , and Escherichia coli.
  • [7] The treating agent according to any one of [1] to [6], wherein the dose of 7-[(3S,4S)-3- ⁇ (cyclopropylamino)methyl ⁇ -4-fluoropyrrolidine-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof per day is 10 mg or more and 250 mg or less.
  • a treating agent for an infection which is one or two or more selected from the group consisting of pharyngitis, laryngitis, tonsillitis, acute bronchitis, pneumonia, secondary infections of chronic respiratory diseases, sinusitis, and tympanitis, and in which pathogenic bacteria are Streptococcus pneumoniae , the treating agent including, as an active ingredient, 7-[(3S,4S)-3- ⁇ (cyclopropylamino)methyl ⁇ -4-fluoropyrrolidine-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof.
  • a method for treating a respiratory infection including administering 7-[(3S,4S)-3- ⁇ (cyclopropylamino)methyl ⁇ -4-fluoropyrrolidine-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof in an amount effective to treat a respiratory infection to a subject in need thereof.
  • pathogenic bacteria causing the respiratory infection are one or two or more types of bacteria selected from the group consisting of bacteria belonging to Staphylococcus sp., bacteria belonging to Streptococcus sp., Moraxella catarrhalis , bacteria belonging to Klebsiella sp., Haemophilus influenzae , and Escherichia coli.
  • pathogenic bacteria causing the respiratory infection are one or two or more types of bacteria selected from the group consisting of bacteria belonging to Staphylococcus sp., bacteria belonging to Streptococcus sp., Moraxella catarrhalis , bacteria belonging to Klebsiella sp., Haemophilus influenzae , and Escherichia coli.
  • pathogenic bacteria causing the respiratory infection are one or two or more types of bacteria selected from the group consisting of bacteria belonging to Staphylococcus sp., bacteria belonging to Streptococcus sp., Moraxella catarrhalis , bacteria belonging to Klebsiella sp., Haemophilus influenzae , and Escherichia coli.
  • a method for treating an infection which is one or two or more selected from the group consisting of pharyngitis, laryngitis, tonsillitis, acute bronchitis, pneumonia, secondary infections of chronic respiratory diseases, sinusitis, and tympanitis, and in which the pathogenic bacteria are Streptococcus pneumoniae , the method including administering 7-[(3S,4S)-3- ⁇ (cyclopropylamino)methyl ⁇ -4-fluoropyrrolidine-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof in an amount effective to treat the respiratory infection to a subject in need thereof.
  • an infection which is one or two or more selected from the group consisting of pharyngitis, laryngitis, tonsillitis, acute bronchitis, pneumonia, secondary infections of chronic respiratory diseases, sinusitis, and tympanitis, and in which the pathogenic bacteria are Streptococcus pneumoniae.
  • a treating agent for an infection which is one or two or more selected from the group consisting of pharyngitis, laryngitis, tonsillitis, acute bronchitis, pneumonia, secondary infections of chronic respiratory diseases, sinusitis, and tympanitis, the treating agent containing 7-[(3S,4S)-3- ⁇ (cyclopropylamino)methyl ⁇ -4-fluoropyrrolidine-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the dose of the compound per day is 75 mg or two times the amount.
  • An infection treating agent containing 7-[(3S,4S)-3- ⁇ (cyclopropylamino)methyl ⁇ -4-fluoropyrrolidine-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the tissue distribution ratio of the compound into an alveolar epithelial lining fluid 1 hour after administration to human is 10 or more.
  • An infection treating agent containing 7-[(3S,4S)-3- ⁇ (cyclopropylamino)methyl ⁇ -4-fluoropyrrolidine-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the tissue distribution ratio of the compound into an alveolar epithelial lining fluid 1 hour after administration to human is 10 or more and 50 or less.
  • the present invention can provide a technique pertaining to a novel respiratory infection treating agent.
  • FIG. 1 is a graph showing the number of bacteria in the lung of mouse after subcutaneous administration of a drug in Test Example 6.
  • FIG. 2 is a graph showing the number of bacteria in the lung of mouse after oral administration of a drug in Test Example 6.
  • a treating agent of the embodiment relates to a respiratory infection treating agent, and for example, can be used for treatment of respiratory infection in human.
  • the respiratory infection means an infection caused at any location of the respiratory organ.
  • the respiratory organ collectively refers to the organ pertaining to respiration, and means the organ from the nasal vestibule to the alveolar through the nasal cavity, the pharynx, the larynx, the trachea, the bronchus, and the bronchiole.
  • Examples of the respiratory infection involved in the treating agent of the embodiment may include one or two or more respiratory infections selected from the group consisting of common cold, pharyngitis, laryngitis, epiglottitis, tonsillitis (including peritonsillitis and peritonsillar abscess), bronchitis (including acute bronchitis, chronic bronchitis, and diffuse panbronchiolitis), pneumonia, secondary infections of chronic respiratory diseases, and bronchiectasis.
  • respiratory infections selected from the group consisting of common cold, pharyngitis, laryngitis, epiglottitis, tonsillitis (including peritonsillitis and peritonsillar abscess), bronchitis (including acute bronchitis, chronic bronchitis, and diffuse panbronchiolitis), pneumonia, secondary infections of chronic respiratory diseases, and bronchiectasis.
  • a target disease of the treating agent in a more preferred embodiment may be one or two or more types of respiratory infections selected from the group consisting of the acute bronchitis, pneumonia, and secondary infections of chronic respiratory diseases, since the compound according to the embodiment can be rapidly transferred to a location where symptom occurs to achieve more effective treatment.
  • Pathogenic bacteria causing the respiratory infection which is the target disease of the treating agent of the embodiment are, for example, one or two or more types of bacteria selected from the group consisting of bacteria belonging to Staphylococcus sp., bacteria belonging to Streptococcus sp., Moraxella ( Branhamella ) catarrhalis , bacteria belonging to Klebsiella sp., bacteria belonging to Enterobacter sp., Haemophilus influenzae , bacteria belonging to Enterococcus sp., Escherichia coli, Pseudomonas aeruginosa, Legionella, Chlamydia, Mycoplasma, Coxiella burnetii, Bordetella pertussis , and anaerobic bacteria.
  • the pathogenic bacteria for which the treating agent of the embodiment is used is more preferably one or two or more types of bacteria selected from the group consisting of bacteria belonging to Staphylococcus sp, bacteria belonging to Streptococcus sp., Moraxella catarrhalis , bacteria belonging to Klebsiella sp., bacteria belonging to Enterobacter sp., Haemophilus influenzae, Legionella pneumophila, C. pneumoniae ( Chlamydophila pneumoniae ), M.
  • bacteria belonging to Staphylococcus sp. bacteria belonging to Streptococcus sp., Moraxella catarrhalis , bacteria belonging to Klebsiella sp., Haemophilus influenzae , and Escherichia coli , and particularly preferably one or two or more types of bacteria belonging to any of Streptococcus sp. and Staphylococcus sp.
  • pathogenic bacteria belonging to Streptococcus sp. may include Pneumococcus, Streptococcus pyogenes , hemolytic streptococcus , and Streptococcus sanguinis .
  • the pathogenic bacteria for which the treating agent of the embodiment is used is preferably Streptococcus pneumoniae .
  • the pathogenic bacteria belonging to Staphylococcus sp. may include Staphylococcus aureus and Staphylococcus epidermidis .
  • the pathogenic bacteria for which the treating agent of the embodiment is used is preferably Staphylococcus aureus .
  • the treating agent of the embodiment can be used for treatment of one or two or more types of respiratory infections which are selected from the group consisting of acute bronchitis, pneumococcus , and secondary infections of chronic respiratory diseases and in which pathogenic bacteria are Streptococcus pneumoniae and/or Staphylococcus aureus.
  • pathogenic bacteria mean a concept including bacteria which have acquired drug resistance.
  • the drug resistance means a phenomenon in which an organism has resistance to a drug and the drug is not effective or is unlikely to be effective.
  • Examples of drug resistance may include resistance to penicillin, resistance to cephem, resistance to carbapenem, resistance to aminoglycoside, resistance to macrolide, resistance to lincomycin, resistance to trimethoprim-sulfa, resistance to tetracycline, resistance to metronidazole, resistance to glycopeptide, resistance to oxazolidinone, resistance to daptomycin, and resistance to quinolone.
  • bacteria which have acquired drug resistance may include penicillin-resistant bacteria such as penicillin-resistant Streptococcus pneumoniae (PRSP), methicillin-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidemidis (MRSE), vancomycin-resistant bacteria such as vancomycin-resistant enterococcus (VRE), macrolide-resistant bacteria such as macrolide-resistant Streptococcus pneumoniae , and quinolone-resistant bacteria such as quinolone-resistant Streptococcus pneumoniae.
  • PRSP penicillin-resistant Streptococcus pneumoniae
  • MRSA methicillin-resistant Staphylococcus aureus
  • MRSE methicillin-resistant Staphylococcus epidemidis
  • vancomycin-resistant bacteria such as vancomycin-resistant enterococcus (VRE)
  • macrolide-resistant bacteria such as macrolide-resistant Streptococcus pneumoniae
  • a disease to be treated by the treating agent of the embodiment may be any of a respiratory infection in which the pathogenic bacteria are non-drug-resistant bacteria and a respiratory infection in which the pathogenic bacteria are bacteria which have acquired drug resistance, and is not particularly limited.
  • the treating agent of the embodiment since the treating agent of the embodiment also exhibits excellent therapeutic effect on a respiratory infection in which the pathogenic bacteria are bacteria which have acquired drug resistance, the pathogenic bacteria causing the target disease of the treating agent of the embodiment may be preferably quinolone-resistant bacteria, and more preferably quinolone-resistant Streptococcus pneumoniae and/or quinolone-resistant Staphylococcus aureus .
  • the treating agent of the embodiment can be used for treatment of one or two or more types of respiratory infections which are selected from the group consisting of acute bronchitis, pneumonia, and secondary infections of chronic respiratory diseases, and in which the pathogenic bacteria are quinolone-resistant Streptococcus pneumoniae and/or quinolone-resistant Staphylococcus aureus.
  • the treating agent of the embodiment may be composed of 7-[(3S,4S)-3- ⁇ (cyclopropylamino)methyl ⁇ -4-fluoropyrrolidine-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof alone.
  • the treating agent of the embodiment may be a pharmaceutical composition containing 7-[(3S,4S)-3- ⁇ (cyclopropylamino)methyl ⁇ -4-fluoropyrrolidine-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof, and another compound acting as an active ingredient, and/or a pharmaceutically acceptable additive.
  • the pharmaceutical composition can contain one or more types of compounds as the other compound acting as an active ingredient and/or as the pharmaceutically acceptable additive.
  • the pharmaceutical composition can be prepared, for example, by mixing 7-[(3S,4S)-3- ⁇ (cyclopropylamino)methyl ⁇ -4-fluoropyrrolidine-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof with one or more types of the compound acting as an active ingredient or the additive.
  • Examples of the pharmaceutically acceptable additive contained with 7-[(3S,4S)-3- ⁇ (cyclopropylamino)methyl ⁇ -4-fluoropyrrolidine-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof may include an excipient, a lubricant, a binder, a disintegrant, a stabilizer, a flavoring agent, and a diluent.
  • additives are not particularly limited as long as they can be used for production of a pharmaceutical preparation, and for example, an additive listed in “Japanese Pharmaceutical Excipients Directory (International Pharmaceutical Excipients Council Japan, YAKUJI NIPPO, LTD. (2007)) can be appropriately used.
  • the treating agent of the embodiment can be administered to a subject such as human in a form well conventionally known as a pharmaceutical form through an administration route well conventionally known as a pharmaceutical route.
  • the treating agent may be orally or non-orally administrated in a form of preparation such as a powder, a tablet, a capsule, a subtle granule, a granule, a syrup, an injection, an ophthalmic liquid, an aqueous nose drop, an aqueous ear drop, or an inhalant liquid.
  • the treating agent of the embodiment may be produced in the form exemplified above, for example, by mixing a physiologically acceptable carrier, excipient, binder, and diluent, and the like with the active ingredient.
  • the dose of 7-[(3S,4S)-3- ⁇ (cyclopropylamino)methyl ⁇ -4-fluoropyrrolidine-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof per day is preferably 10 mg or more and 250 mg or less, more preferably 20 mg or more and 200 mg or less, further preferably 30 mg or more and 160 mg or less, still more preferably 40 mg or more and 100 mg or less, yet more preferably 50 mg or more and 90 mg or less, and particularly preferably 60 mg or more and 80 mg or less.
  • the treating agent in a daily dose may be administrated once or in divided doses two to three times. It is preferable that the treating agent be administrated once per day. When the effect is insufficient, the treating agent may be used in an amount which is two times the daily dose.
  • loading administration may be performed.
  • the loading administration means an administration design in which the daily dose or the number of administration per day is increased at the early stage of administration to rapidly reach the target blood level.
  • the early stage of administration means the first to third days of initiation of the administration, preferably the first to second days, and further preferably the first day of initiation of the administration.
  • an increased daily dose an amount which is two times the daily dose is preferably used.
  • the amount which is two times the daily dose be used on the first day of initiation of administration.
  • a pharmaceutically acceptable salt of 7-[(3S,4S)-3- ⁇ (cyclopropylamino)methyl ⁇ -4-fluoropyrrolidine-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid is not particularly limited as long as it is a pharmacologically acceptable salt.
  • Examples thereof may include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, salts with organic acids such as maleic acid, fumaric acid, succinic acid, malic acid, malonic acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, acetic acid, trifluoroacetic acid, and tartaric acid, and salts with metals such as sodium, potassium, magnesium, calcium, aluminum, cesium, chromium, cobalt, copper, iron, zinc, platinum, and silver.
  • a hydrochloride salt is particularly preferable from the viewpoint of stability and the distribution ratio to the lung.
  • this embodiment can provide a technique pertaining to a novel treatment of a respiratory infection.
  • the maximum plasma concentration of 7-[(3S,4S)-3- ⁇ (cyclopropylamino)methyl ⁇ -4-fluoropyrrolidine-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof after administration of the treating agent according to the embodiment to human with a respiratory infection may be 3 ⁇ g/mL or less.
  • the dose of 7-[(3S,4S)-3- ⁇ (cyclopropylamino)methyl ⁇ -4-fluoropyrrolidine-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof per day may be 75 mg or two times the amount.
  • the maximum plasma concentration of 7-[(3S,4S)-3- ⁇ (cyclopropylamino)methyl ⁇ -4-fluoropyrrolidine-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof after administration of the treating agent according to the embodiment to human with a respiratory infection may be 0.5 ⁇ g/mL or more and 1.5 ⁇ g/mL or less, and in a more preferable aspect, the maximum plasma concentration may be 0.7 ⁇ g/mL or more and 1.2 ⁇ g/mL or less.
  • the dose of 7-[(3S,4S)-3- ⁇ (cyclopropylamino)methyl ⁇ -4-fluoropyrrolidine-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof per day may be 75 mg.
  • the treating agent in a smaller dose than that of another drug can be expected to be effective against foci in the lung tissue or the like. Accordingly, a reduction in side effect, formation of a small preparation which can be easily administrated, prevention of development of resistant bacteria, and the like can be expected.
  • the treating agent of the embodiment also exhibits excellent therapeutic effect on a respiratory infection in which the pathogenic bacteria are bacteria which have acquired drug resistance, such as quinolone-resistant bacteria.
  • the treating agent of the embodiment has the property that the frequency of development of resistant bacteria is lower than those in the other quinolone compounds.
  • this embodiment can provide a respiratory infection treating agent which has excellent effectiveness and safety.
  • reaction liquid A mixture (reaction liquid) of ethyl 3-(2,4,5-trifluoro-3-methoxy)phenyl-3-oxopropanate (1397.4 mg, 5.06 mmol), acetic anhydride (13.4 mL), and triethyl ortho[ 14 C] formate (293 mCi, 851 ⁇ L, 758 mg, 5.05 mmol, density: 0.891 g/mL) was heated and refluxed for 1 hour under a nitrogen atmosphere. The reaction liquid was cooled to room temperature, toluene (17 mL) was added to the reaction liquid, and the obtained mixture was concentrated under reduced pressure using a rotary evaporator. To the residue, toluene (17 mL) was added, and the mixture was concentrated under reduced pressure using a rotary evaporator. This operation was repeated 4 times, to obtain a yellow oily product.
  • reaction liquid dimethylsulfoxide (13.4 mL), 2-fluoroethylaminehydrochloride (1259.84 mg, 12.7 mmol, and potassium carbonate (1745.4 mg, 12.6 mmol) were added to obtain a reaction liquid.
  • the reaction liquid was stirred at 47° C. for 3 hours under a nitrogen atmosphere.
  • potassium carbonate (1752.9 mg, 12.7 mmol) was added, and the mixture was stirred at 78° C. for 1 hour, and then stirred at room temperature overnight, to obtain a reaction liquid.
  • Triethyl orthoformate was used instead of triethyl ortho[ 14 C]orthoformate, and the same operation as in Reference Example 1-1 was performed. Thus, 6,7-difluoro-1-(2-fluoroethyl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (compound A-2) was obtained.
  • reaction liquid A mixed liquid (reaction liquid) of boric acid (954 mg, 15.4 mmol), acetic anhydride (8.4 mL), and zinc chloride (7.1 mg, 0.05 mmol) was stirred at room temperature for 10 minutes under a nitrogen atmosphere.
  • the compound A-1 878 mg, 2.65 mmol
  • the compound A-2 400 mg, 1.22 mmol
  • the reaction liquid was stirred at 55° C. for 2 hours under a nitrogen atmosphere.
  • the reaction liquid was cooled to 30° C., and acetone (6.3 mL) was added to the reaction liquid.
  • reaction liquid A mixture (reaction liquid) of (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (880 mg, 3.81 mol), triethylamine (2.9 mL, 2.1 g, 20.8 mmol), and dimethylsulfoxide (14.9 mL) was stirred at room temperature for 10 minutes under a nitrogen atmosphere.
  • the compound B prepared in Reference Example 2 1489.2 mg, 3.46 mmol
  • ethyl acetate (30 mL), water (30 mL), and an aqueous 2 mol/L sodium hydroxide solution (3.0 mL, 6.00 mmol) were added, and the mixture was stirred at room temperature for 5 minutes, and separated into an aqueous layer and an organic layer.
  • the aqueous layer was washed twice with ethyl acetate (30 mL), and the combined organic layer was washed with water (30 mL) and saturated brine (30 mL), dried with anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the product collected by filtration (569.2 mg, 47 mCi, 82.6 ⁇ Ci/mg), the concentrated mother liquid (228.3 mg, 17.9 mCi, 78.4 ⁇ Ci/mg), and a compound D (383.8 mg) were combined using ethanol (42 mL) and water (3.6 mL).
  • the resulting mixture was stirred at 80° C. under a nitrogen atmosphere until the solid was completely dissolved.
  • the mixed liquid was gradually cooled to 39 to 40° C. at a speed of 1° C./min.
  • the mixed liquid was held to 39° C. for 30 minutes, and then gradually cooled to 23° C. at a speed of 1° C./min.
  • the mixed liquid was held at room temperature for 30 minutes, and then held for 45 minutes under ice-cooling, to obtain a precipitate.
  • the precipitate was collected by filtration, and washed twice with ethanol (3 mL), to obtain a white solid.
  • the white solid was dried under reduced pressure, to obtain a compound C.
  • the compound C (10.83 mg/kg) (solvent: water) was single orally administrated to a SD rat under fasting. 1, 6, and 24 hours after the administration, the lung tissue and the plasma were collected.
  • the lung tissue was dried and treated by a sample oxidizer system (Sample Oxidizer: Model 307, PerkinElmer Inc., glass vial: 20 mL, Wheaton Industries, carbon dioxide absorbent: Carbo-Sorb 8 mL, PerkinElmer Inc., scintillation cocktail: Permafluor 12 mL, PerkinElmer Inc.), and the radioactivity concentration was measured.
  • the compound C distributed into the lung tissue rapidly after administration, and 1 hour after the administration, the tissue distribution ratio into the lung was as very high as “3.7”.
  • the measurement was as follows. Healthy adult male volunteers were given oral single dose of compound D (75 mg). The bronchoalveolar lavage fluid and blood samples were collected from the subjects at 1, 2, 4, 6, and 24 hours after the administration. The collection of the fluid and blood samples was carried out at each time point for six subjects. The bronchoalveolar lavage fluid was centrifuged to separate from epithelial lining fluid and alveolar macrophages for measurement of the drug concentration. The concentrations of compound D in lung tissue and plasma were measured by LC/MS/MS. The mean ratios of lung tissue-to-plasma concentration are shown as tissue distribution ratio in Table 2 at each sampling points.
  • the tissue distribution ratio of compound D in epithelial lining fluid and alveolar macrophages is extremely high with the ranges of 15.0-22.5 and 18.5-56.4, respectively.
  • the compound D can reach to the respiratory infectious lesion with high concentration and indicate strong antibiotic action against the target pathogens causing respiratory tract infection. Therefore, it is suggested that compound D is particularly excellent for the treatment of respiratory tract infection.
  • tissue distribution ratio of compound D at 1 hour after administration in epithelial lining fluid and alveolar macrophages is 22.5 and 31.9, respectively, which shows significantly good distribution.
  • Initial antimicrobial effect after infection is important to the respiratory tract infection treatment.
  • Compound D is distributed rapidly to intrapulmonary infectious lesion in one hour after administration. Therefore, compound D is especially useful for the treatment of respiratory tract infection.
  • the tissue distribution ratio inhuman of levofloxacin in the bronchoalveolar lavage fluid is 1.1 to 3.0 (0.5 to 8 hours after administration), and the tissue distribution ratio in the alveolar macrophages is 4.1 to 18.9 (0.5 to 24 hours after administration) (from the interview forms of Cravit (registered trademark) tablets 250 mg and 500 mg, and Cravit (registered trademark) granules 10%).
  • the tissue distribution ratio in human of garenoxacin in the epithelial lining fluid is 0.95 ⁇ 0.41 (2.5 to 3.5 hours after administration), and the tissue distribution ratio in the alveolar macrophages is 11.15 ⁇ 8.16 (2.5 to 3.5 hours after administration) (from the interview form of Geninax (registered trademark) tablets 200 mg).
  • the tissue distribution ratio in human of moxifloxacin in the airway secretory fluid is 6.78 (3 hours after administration), and the tissue distribution ratio in the alveolar macrophages is 18.59 (3 hours after administration) (from the interview form of Avelox (registered trademark) tablets 400 mg). These datas indicate that the tissue distribution ratio of compound D is remarkably high, compared with marketed quinolone.
  • the daily dosage can be set to be lower compared with the other quinolone compounds. It is suggested that side effects can be reduced.
  • compound D Due to the high distribution ratio into lung tissue, compound D can provide high concentration in the respiratory infectious lesion and can be contributed to preventing appearance of antimicrobial resistant bacteria.
  • an infection treating agent containing 7-[(3S,4S)-3- ⁇ (cyclopropylamino)methyl ⁇ -4-fluoropyrrolidine-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof and having a tissue distribution ratio of the compound into an alveolar epithelial lining fluid 1 hour after administration in administration to human of 10 or more can be configured.
  • the tissue distribution ratio into alveolar epithelial lining fluid after 1 hour of administration is preferably within the range of 10 or more 50 or more less, and more preferably 15 or more 40 or more less.
  • the inhibitory activity of the compound D against DNA gyrase derived from S. pneumoniae IID553 was measured on the basis of the production amount of Supercoiled form DNA using Relaxed pBR322 as a substrate in accordance with Antimicrob. Agents Chemother. 47: 77-81 (2003).
  • the inhibitory activity of the compound D against Topoisomerase IV was measured based on the production amount of Decatenated form DNA using Kinetoplast DNA as a substrate.
  • the inhibitory activities of levofloxacin (LVFX) and garenoxacin (GRNX) were measured. The results were compared. The results are shown in Table 3.
  • the 50% inhibitory concentration (IC 50 ) value in Table 3 means an average value of results measured three times ⁇ SD.
  • the compound D is more excellent than levofloxacin and garenoxacin.
  • the strain No. 1 is anon-quinolone-resistant strain (parent strain), and the strains No. 2 to 7 area quinolone-resistant strain.
  • the compound D maintains excellent activity also against the quinolone-resistant strain as compared with the other quinolone compounds.
  • the compound D exhibits high activity against the strains Nos. 6 ( S. pneumoniae ST9941) and 7 ( S. pneumoniae 5N9981), which are a double mutant strain, as compared with the other quinolone compounds.
  • S. pneumoniae KY-9 was inoculated at 7.4 ⁇ 10 5 CFU/mouse via the respiratory tract into the lung in a mouse in which cyclophosphamide had been administrated. 2.9 to 3.1 hours, 17.3 to 19.1 hours, and 24.4 to 26.1 hours after the inoculation, the drug (the compound D, levofloxacin, or garenoxacin) was subcutaneously administrated (SC) or orally administrated (PO) three times in total. The number of bacteria in the lung 16.5 to 17.0 hours after the final administration was measured. The results are shown in FIGS. 1 and 2 .
  • CFU is an abbreviation of Colony Forming Unit, and represents the unit of number of bacteria.
  • Log CFU/Lung means the number of viable bacteria in the lung. Log CFU/Lung was determined as follows. The lung obtained from the mouse was homogenated to obtain a bacterial culture. The bacterial culture was appropriately diluted, applied to an agar plate medium, and cultured. Log CFU/Lung was determined on the basis of the number of developed colonies.
  • the therapeutic effects of the compound D and garenoxacin in 25 mg/kg administration groups were compared.
  • the number of viable bacteria in the lung for the compound D is 10 2.6 CFU/Lung, and the number for garenoxacin is 10 5.5 CFU/Lung. An about 1,000 times difference is observed.
  • the minimum inhibitory concentration (MIC) of the compound D against Streptococcus pneumoniae ( S. pneumoniae KY-9) is comparable with garenoxacin (see Table 5), but the compound D having excellent tissue distribution into the lung exerts a therapeutic effect which is higher than that of garenoxacin.
  • FIG. 2 is a graph showing the number of bacteria in the lung after oral administration. Similarly to the subcutaneous administration, the therapeutic effect of the compound D is excellent as compared with garenoxacin and levofloxacin.
  • the compound D is effective as a treating agent for a disease in which the pathogenic bacteria are Streptococcus pneumoniae .
  • the disease in which the pathogenic bacteria are Streptococcus pneumoniae may include otolaryngologic diseases such as sinusitis and tympanitis, in addition to respiratory infections such as pharyngitis, laryngitis, tonsillitis, acute bronchitis, pneumonia, and secondary infections of chronic respiratory diseases.
  • a treating agent for an infection which is one or two or more selected from the group consisting of pharyngitis, laryngitis, tonsillitis, acute bronchitis, pneumonia, secondary infections of respiratory diseases, sinusitis, and tympanitis and in which the pathogenic bacteria are Streptococcus pneumoniae
  • the treating agent containing, as an active ingredient, 7-[(3S,4S)-3- ⁇ (cyclopropylamino)methyl ⁇ -4-fluoropyrrolidine-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof
  • Cmax maximum drug concentration
  • AUC area under the curve
  • the clinical efficacy (cure rate) of the compound D was 90.0%. This efficacy rate is not less than those of garenoxacin and levofloxacin.
  • compound D has very excellent distribution into lung tissue in human. Therefore, compound D can indicate high therapeutic efficacy even with low plasma concentration. Compound D does not need high plasma concentration unlike another drug. For this reason, the dose of compound D can be reduced, and it can be expected to reduce side effects and miniaturize the formulation which can be easily administrated.
  • the frequencies of development of bacteria resistant to the compound D, levofloxacin, garenoxacin, and ciprofloxacin for S. aureus ATCC29213, S. pneumoniae ATCC49619, and E coli ATCC25922 were investigated.
  • a drug having a concentration 4, 8, and 16 times (4 ⁇ MIC, 8 ⁇ MIC, and 16 ⁇ MIC) the MIC value of each strain the frequency of development of resistant bacteria was investigated.
  • S. aureus ATCC29213 is Staphylococcus aureus
  • S. pneumoniae ATCC49619 is Streptococcus pneumoniae
  • E. coli ATCC25922 is Escherichia coli.
  • Escherichia coli is known as a main causative microorganism of chronic respiratory tract infection.
  • the frequency of development of resistant bacteria was calculated by dividing the number of colonies developed on an agar medium having each drug concentration by the number of initially inoculated bacteria.
  • aureus COMPOUND D 0.008 ⁇ 2.1 ⁇ 10 ⁇ 9 ⁇ 2.1 ⁇ 10 ⁇ 9 ⁇ 2.1 ⁇ 10 ⁇ 9 ATCC29213 LVFX 0.125 ⁇ 2.1 ⁇ 10 ⁇ 9 ⁇ 2.1 ⁇ 10 ⁇ 9 ⁇ 2.1 ⁇ 10 ⁇ 9 GRNX 0.015 8.2 ⁇ 10 ⁇ 9 * ⁇ 2.1 ⁇ 10 ⁇ 9 ⁇ 2.1 ⁇ 10 ⁇ 9 CPFX 0.25 6.2 ⁇ 10 ⁇ 9 * 3.1 ⁇ 10 ⁇ 9 * ⁇ 2.1 ⁇ 10 ⁇ 9 E.
  • bacteria resistant to levofloxacin were developed for E. coli ATCC25922, and bacteria resistant to garenoxacin were developed for S. aureus ATCC29213.
  • bacteria resistant to ciproxacin were developed.
  • the inhibitory activities of the compound D against DNA gyrase derived from S. aureus and quinolone-resistant S. aureus were measured on the basis of the production amount of Supercoiled form DNA using Relaxed pBR322 as a substrate in accordance with Antimicrob. Agents Chemother. 45: 3544-3547 (2001).
  • the inhibitory activity of the compound D against Topoisomerase IV was measured on the basis of the production amount of Decatenated form DNA using Kinetoplast DNA as a substrate. The measurement was performed in the same manner as in Test Example 3. Similarly, the inhibitory activities of ciproxacin, levofloxacin, and garenoxacin were measured. The results were compared.
  • IC 50 VALUE AVERAGE OF THREE MEASURED VALUES OR AVERAGE ⁇ SD
  • the antibacterial activities in vitro of the compound D, levofloxacin, garenoxacin, and ciprofloxacin against a quinolone-resistant strain of Streptococcus pneumoniae were measured in accordance with a CLSI agar microdilution method or a CLSI microdilution method.
  • aureus MS5935 2nd 2nd step grlA gyrA Ser84Leu Ser80Phe 0.125 8 2 16 DOUBLE MUTANT STRAIN
  • the compound D maintains excellent activity also against the quinolone-resistant strain in addition to a parent strain (non-quinolone-resistant strain) as compared with the other quinolone compounds.
  • the MIC of the compound D against high quinolone-resistant S. aureus (4th step grlA, gyrA, grlA, gyrA quadruple mutant strains) was 2 ⁇ g/mL, and the potency (action strength) 16 or more times those of the other quinolone compounds was observed.
  • the embodiment can provide a novel respiratory infection treating agent containing 7-[(3S,4S)-3- ⁇ (cyclopropylamino)methyl ⁇ -4-fluoropyrrolidine-1-yl]6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof, which is industrially useful.

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