WO2018230686A1 - Therapeutic agent for aspiration pneumonia, lung suppuration, or lung abscess - Google Patents
Therapeutic agent for aspiration pneumonia, lung suppuration, or lung abscess Download PDFInfo
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- WO2018230686A1 WO2018230686A1 PCT/JP2018/022846 JP2018022846W WO2018230686A1 WO 2018230686 A1 WO2018230686 A1 WO 2018230686A1 JP 2018022846 W JP2018022846 W JP 2018022846W WO 2018230686 A1 WO2018230686 A1 WO 2018230686A1
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Classifications
-
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- the present invention relates to a therapeutic agent for aspiration pneumonia, pulmonary abscess or lung abscess.
- Patent Document 1 discloses a quinolone carboxylic acid derivative represented by the general formula (1) (Patent Document 1).
- R 1 is an alkyl group having 1 to 6 carbon atoms which may be substituted with one or more halogen atoms, and 3 to 6 carbon atoms which may be substituted with one or more halogen atoms.
- R 2 is a hydrogen atom; alkyl group, 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 represents a hydrogen atom or a halogen atom,
- Patent Document 1 discloses 7-[(3S, 4S) -3- ⁇ (cyclopropylamino) methyl ⁇ -4-fluoropyrrolidin-1-yl] -6 as one of the quinolonecarboxylic acid derivatives described above. -Fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid is disclosed. The hydrochloride is disclosed in Patent Document 2.
- aspiration pneumonia is one of the respiratory infections.
- Aspiration pneumonia is a disease that accounts for the majority of pneumonia in the elderly and is a serious disease that is refractory, relapsed, and has a high fatality rate (Non-patent Document 1).
- Anaerobic bacteria, Staphylococcus aureus, and enterobacteria are mentioned as the causative bacteria of aspiration pneumonia (Non-patent Document 1), but a method for effectively treating aspiration pneumonia has been established so far. Absent.
- the quinolone preparations currently on the market include levofloxacin, ciprofloxacin, pazufloxacin, moxifloxacin, sitafloxacin and garenoxacin.
- Non-patent Document 2 For aspiration pneumonia, which is a high-severity disease, most of the initial treatment uses injectable preparations.
- levofloxacin, ciprofloxacin and Pazufloxacin has insufficient antibacterial activity against anaerobic bacteria and is not recommended for use in patients suspected of aspiration pneumonia (Non-patent Document 2).
- sitafloxacin, moxifloxacin and galenoxacin may be effective against anaerobic bacterial infections (Non-Patent Documents 3 to 5), but high for aspiration pneumonia There are no reports of articles with evidence, and no effective treatment has been established to date.
- Non-patent Document 6 As in the case of aspiration pneumonia, a lung abscess is an example of a respiratory infection mainly caused by anaerobic bacteria (Non-patent Document 6). Although there are reports that therapeutic effects are recognized for moxifloxacin and pazufloxacin (Non-Patent Documents 3 to 4 and Non-Patent Document 7), it has not been established as an effective treatment method to date.
- An object of the present invention is to provide a novel therapeutic agent for respiratory infections.
- the inventors of the present invention have made extensive studies on the above-mentioned problems, and found that 7-[(3S, 4S) -3- ⁇ (cyclopropylamino) methyl ⁇ -4-fluoropyrrolidin-1-yl] -6-fluoro-1 Found that-(2-fluoroethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid is extremely effective as a treatment for aspiration pneumonia, pulmonary abscess or lung abscess The present invention has been reached.
- the gist of the present invention is as follows. [1] 7-[(3S, 4S) -3- ⁇ (cyclopropylamino) methyl ⁇ -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy- A therapeutic agent for aspiration pneumonia, pulmonary abscess or lung abscess containing 4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
- a therapeutic agent for pulmonary abscess or lung abscess comprising 4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
- the causative bacteria of the aspiration pneumonia, pulmonary abscess or lung abscess are bacteria belonging to the genus Prevotella, bacteria belonging to the genus Peptostreptococcus, bacteria belonging to the genus Parvimonas, bacteria belonging to the genus Peptoniphyllus, genus Finegordia
- the therapeutic agent according to [1] which is one type or two or more types of bacteria selected from the group consisting of bacteria belonging to genus and bacteria belonging to the genus Fusobacterium.
- the bacteria causing the aspiration pneumonia are bacteria belonging to the genus Prebotella, bacteria belonging to the genus Peptostreptococcus, bacteria belonging to the genus Parvimonas, bacteria belonging to the genus Peptoniphyrus, bacteria belonging to the genus Finegordia, and Fusobacterium genus
- the therapeutic agent according to [2] which is one or more bacteria selected from the group consisting of bacteria belonging to.
- the pathogenic bacteria of the pulmonary abscess or lung abscess are bacteria belonging to the genus Prebotella, bacteria belonging to the genus Peptostreptococcus, bacteria belonging to the genus Parvimonas, bacteria belonging to the genus Peptoniphyrus, bacteria belonging to the genus Finegordia, and
- the bacteria causing aspiration pneumonia, pulmonary abscess or lung abscess belong to a bacterium belonging to the genus Bacteroides, a bacterium belonging to the genus Prevotella, a bacterium belonging to the genus Porphyromonas, a bacterium belonging to the genus Fusobacterium, or the genus Leptotricia
- the therapeutic agent according to [1] which is two or more types of bacteria.
- the pathogenic bacterium of the aspiration pneumonia is selected from the group consisting of a bacterium belonging to the genus Bacteroides, a bacterium belonging to the genus Prebotella, a bacterium belonging to the genus Parvimonas, a bacterium belonging to the genus Bayonella and the genus Actinomyces,
- the therapeutic agent according to [2] which is two or more kinds of bacteria.
- the pulmonary abscess or pulmonary abscess causing bacteria are bacteria belonging to the genus Bacteroides, bacteria belonging to the genus Prebotella, bacteria belonging to the genus Porphyromonas, bacteria belonging to the genus Fusobacterium, bacteria belonging to the genus Leptotricia, peptostreptococcus [3] which is one or more bacteria selected from the group consisting of a bacterium belonging to the genus, a bacterium belonging to the genus Parvimonas, a bacterium belonging to the genus Bayonella, a bacterium belonging to the genus Tisierella, and a Streptococcus anginasus group, The therapeutic agent described.
- a therapeutic agent for aspiration pneumonia, pulmonary abscess or lung abscess comprising administering to a patient methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof can be provided.
- the therapeutic agent of this embodiment relates to a therapeutic agent for respiratory diseases, but particularly relates to a therapeutic agent for respiratory infections. More specifically, the therapeutic agent of this embodiment is 7-[(3S, 4S) -3- ⁇ (cyclopropylamino) methyl ⁇ -4-fluoropyrrolidin-1-yl] -6-fluoro-1- Aspiration comprising administering (2-fluoroethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof to a patient, including a human.
- the present invention relates to a therapeutic agent for pneumonia, pulmonary abscess or lung abscess.
- a respiratory infection refers to an infection that occurs at any site in the respiratory tract.
- the respiratory organ is a general term for organs related to respiration, and refers to organs from the nasal vestibule to the alveoli via the nasal cavity, pharynx, larynx, trachea, bronchi, and bronchioles.
- aspiration pneumonia is a respiratory condition including swelling and infection of the lungs and airways, and is considered to be caused by inhaling harmful substances.
- Patients with aspiration pneumonia may have symptoms such as coughing and dyspnea.
- a patient with aspiration pneumonia means a person who satisfies the following criteria.
- ⁇ A clear infiltrative shadow that appeared acutely on chest X-rays or CT images is observed.
- ⁇ A clear aspiration has been confirmed, repetition of bugs has been confirmed, dysfunction in the swallowing function evaluation test has been confirmed, or a complication or history of a disease with the possibility of swallowing dysfunction
- Symptoms and inflammation that are characteristic of aspiration pneumonia include cough, purulent sputum, moist rales, dyspnea, fever, CRP positive, leukocytosis, hypoxemia and the like.
- pulmonary abscess is a necrotizing pulmonary infection which is also called a lung abscess and is thought to be caused by inhalation of bacteria in the mouth and throat into the lungs.
- Patients with pulmonary abscess may have symptoms such as fatigue, loss of appetite, night sweats, fever, weight loss, and cough with sputum.
- a patient with pulmonary abscess means a person who satisfies the following criteria. ⁇ On chest X-rays or CT images, massive shadows or shadows with cavities inside (nodular shadows, tumor shadows) are observed.
- pulmonary abscess and lung abscess include cough, purulent sputum, moist rales, dyspnea, fever, CRP positive, leukocytosis, hypoxemia and the like.
- Non-patent Document 2 an injection of a quinolone compound such as levofloxacin, ciprofloxacin or pazufloxacin is considered not suitable as a therapeutic agent for aspiration pneumonia.
- Non-patent Document 2 the applicant is not able to use 7-[(3S, 4S) -3- ⁇ (cyclopropylamino) methyl ⁇ -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8- Methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and pharmaceutically acceptable salts thereof are effective against anaerobic pathogens and effective in the treatment of aspiration pneumonia I found out.
- bacteria belonging to the genus Bacteroides (genus Bacteroides), bacteria belonging to the genus Prevotella (genus Prevotella), genus Porphyromonas (genus Porphyromonas) ), Bacteria belonging to the genus Fusobacterium (genus Fusobacterium), bacteria belonging to the genus Leptotrichia (genus Leptotrichia), bacteria belonging to the genus Peptostreptococcus (genus Peptostreptococcus), bacteria belonging to the genus Parvimonas (genus Parvimonas), genus Bayonella (Veillonella), bacteria belonging to the genus Tissierella (genus Tissierella), bacteria belonging to the genus Peptonitphilus (genus Peptonitphilus), bacteria belonging to the genus Finegoldia (genus Finegoldia)
- bacteria that cause aspiration pneumonia include bacteria belonging to the genus Prevotella (genus Prevotella), bacteria belonging to the genus Peptostreptococcus (genus Peptostreptococcus), bacteria belonging to the genus Parvimonas (genus Parvimonas), and the genus Peptonifilus (genus Peptonitphilus)
- bacteria belonging to the genus Finegoldia bacteria belonging to the genus Fusobacterium, bacteria belonging to the genus Bacteroides, bacteria belonging to the genus Streptococcus, and the like.
- the causative bacteria of aspiration pneumonia are the bacteria belonging to the genus Bacteroides, the bacteria belonging to the genus Prevotella, the bacteria belonging to the genus Parvimonas, the bacteria belonging to the genus Bayonella, or the genus Actinomyces. 7-[(3S, 4S) -3- ⁇ (cyclopropylamino) methyl ⁇ -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8
- the high therapeutic effect of -methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid is exerted.
- bacteria that cause pulmonary abscess or lung abscess include bacteria belonging to the genus Prevotella (genus Prevotella), bacteria belonging to the genus Peptostreptococcus, bacteria belonging to the genus Parvimonas (genus Parvimonas), ), Bacteria belonging to the genus Finegoldia (genus Finegoldia), bacteria belonging to the genus Fusobacterium (genus Fusobacterium), bacteria belonging to the genus Bacteroides (genus Bacteroides), bacteria belonging to the genus Streptococcus, and the like.
- the causative bacteria of pulmonary abscess or lung abscess are bacteria belonging to the genus Prevoterra, bacteria belonging to the genus Porphynomonas, bacteria belonging to the genus Fusobacterium, bacteria belonging to the genus Leptotricia, 7-[(3S, 4S) -3- ⁇ (cyclopropylamino) in the case of a bacterium belonging to the genus Peptostreptococcus, a bacterium belonging to the genus Parvimonas, a bacterium belonging to the genus Bayonella, a bacterium belonging to the genus Tisierella, or the Streptococcus anginasus group ) Methyl ⁇ -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1,4
- bacteria belonging to the genus Prebotella include, for example, P. denticola, P. loescheii, P. melaninogenica, P. intermedia, P. nigrescens, P. pallens, P. buccae, P. oris, P. buccalis, P. oralis, P. Bivia, P. disiens, P. pleuritidis, P. bergensis, P. timonensis, or P. nanceiencis genus.
- bacteria belonging to the genus Parvimonas include P. micra. 7-[(3S, 4S) -3- ⁇ (cyclopropylamino) methyl ⁇ -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo More preferably, from the viewpoint of the therapeutic effect of 1,4-dihydroquinoline-3-carboxylic acid, the cause of aspiration pneumonia, pulmonary abscess or lung abscess is P. micra.
- Peptoniphilus asaccharolyticus examples include Peptoniphilus asaccharolyticus, Peptoniphilus ivorii, Peptoniphilus lacrimalis, or Peptoniphilus harei. 7-[(3S, 4S) -3- ⁇ (cyclopropylamino) methyl ⁇ -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo More preferably, from the viewpoint of the therapeutic effect of 1,4-dihydroquinoline-3-carboxylic acid, the cause of aspiration pneumonia, pulmonary abscess or lung abscess is Peptoniphilus asaccharolyticus.
- Examples of bacteria belonging to the genus Finegordia include Finegoldia magna. 7-[(3S, 4S) -3- ⁇ (cyclopropylamino) methyl ⁇ -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo From the viewpoint of the therapeutic effect of 1,4-dihydroquinoline-3-carboxylic acid, more preferably, the cause of aspiration pneumonia, pulmonary abscess or lung abscess is Finegoldia magna.
- Examples of the bacteria belonging to the genus Fusobacterium include F. necrophorum, F. nucleatum, F. mortiferum, and F. varium. 7-[(3S, 4S) -3- ⁇ (cyclopropylamino) methyl ⁇ -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo From the viewpoint of the therapeutic effect of 1,4-dihydroquinoline-3-carboxylic acid, more preferably, the cause of pulmonary abscess or lung abscess is F. nucleatum or F. necrophorum.
- B. fragilis is the causative agent of pulmonary abscess or lung abscess.
- bacteria belonging to the genus Porphyromonas include P. gingivalis, P. endodontalis, P. asaccharolytica, P. levii, or P. uenonis. 7-[(3S, 4S) -3- ⁇ (cyclopropylamino) methyl ⁇ -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo From the viewpoint of the therapeutic effect of 1,4-dihydroquinoline-3-carboxylic acid, more preferably, the pulmonary abscess or pulmonary abscess pathogen is P. gingivalis or P. endodontalis.
- bacteria belonging to the genus Leptotricia examples include L. buccalis, L. hofstadii, L. hongkongensis, L. shahii, L. goodfellowii, L. trevisanii, or L. wadei. 7-[(3S, 4S) -3- ⁇ (cyclopropylamino) methyl ⁇ -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo From the viewpoint of the therapeutic effect of 1,4-dihydroquinoline-3-carboxylic acid, more preferably, the cause of pulmonary abscess or lung abscess is L. buccalis.
- the bacteria belonging to the genus Bayonella examples include V. parvula, V. atypica, and V. montpelliensis.
- bacteria belonging to the genus Tissierella include T. creatinini, T. creatinophila, or T. praeacuta. 7-[(3S, 4S) -3- ⁇ (cyclopropylamino) methyl ⁇ -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo From the viewpoint of the therapeutic effect of 1,4-dihydroquinoline-3-carboxylic acid, more preferably, the cause of pulmonary abscess or lung abscess is T. creatinini.
- bacteria belonging to the Streptococcus anginosas group examples include S. intermedius or S. constellatus. 7-[(3S, 4S) -3- ⁇ (cyclopropylamino) methyl ⁇ -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo
- the pathogenic bacteria of pulmonary abscess or lung abscess are S. intermedius or S. constellatus.
- Actinomyces As a bacterium belonging to the genus Actinomyces, for example, A. europaeus, A. georgiae, A. gerencseriae, A. graevenitzii, A. israelii, A. meyeri, A. naeslundii, A. neuii, A. odontolyticus, A. radicidentis , A. radingae, A. turicensis, A. urogenitalis, A. viscocus, or Actinomyces sp..
- the causative bacterium is a concept including a bacterium that has acquired drug resistance.
- Drug resistance means a phenomenon in which an organism has resistance to a drug and the drug does not work or becomes difficult to work.
- Examples of drug resistance include penicillin resistance, cephalosporin resistance, carbapenem resistance, aminoglycoside resistance, macrolide resistance, lincomycin resistance, trimethoprim-sulfamethoxazole resistance, tetracycline resistance, metronidazole resistance, glycopeptide resistance, oxazolidinone resistance, Examples include daptomycin resistance or quinolone resistance. *
- additives contained with -methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid include, for example, excipients, lubricants, binders, disintegrants, stable Agents, flavoring agents, and diluents. These additives are not particularly limited as long as they can be used for the production of pharmaceutical preparations. For example, they are described in the Pharmaceutical Additives Dictionary “Japan Pharmaceutical Additives Association, Yakuji Nippo (2007)”. Can be used as appropriate.
- the therapeutic agent of the present embodiment can be administered to a subject such as a human by applying conventionally well-known pharmacological forms and administration routes.
- a subject such as a human by applying conventionally well-known pharmacological forms and administration routes.
- powders, tablets, capsules, fine granules, granules , Syrups, injections, ophthalmic solutions, aqueous nasal drops, aqueous ear drops, inhalation solutions and the like can be administered orally or parenterally.
- the therapeutic agent of this embodiment can be produced by mixing the active ingredient with a physiologically acceptable carrier, excipient, binder, diluent, etc., for example, in the dosage form as exemplified above.
- the maximum daily dose is preferably 300 mg or less, 250 mg or less, 200 mg or less, or 175 mg or less. 7-[(3S, 4S) -3- ⁇ (cyclopropylamino) methyl ⁇ -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo
- the daily dose of 1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof is, for example, from 10 mg to 300 mg, more preferably from 20 mg to 250 mg, still more preferably Is from 50 mg to 200 mg, even more preferably from 100 mg to 200 mg, even more preferably from 125 mg to 175 mg, particularly preferably 150 mg.
- the dose per day is 7-[(3S, 4S) -3- ⁇ (cyclopropylamino) methyl ⁇ -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2
- a pharmaceutically acceptable salt of (fluoroethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid is used, the value converted into a free form is used.
- the daily dose may be administered once or divided into 2 to 3 times, but once daily administration is preferred. If the effect is insufficient, a dose twice the daily dose may be used.
- the loading administration means an administration design for reaching a target blood concentration at an early stage by increasing the daily dosage or increasing the number of daily administrations at the initial stage of administration.
- the initial period of administration means the first day to the third day of the start of administration, preferably the first day to the second day of the start of administration, and more preferably the first day of the start of administration.
- as an increase in daily dose preferably twice the daily dose is used.
- the daily dose of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof is 300 mg on the administration start date in terms of free form, After the first day, it is 150 mg.
- 1,4-dihydroquinoline-3-carboxylic acid hydrochloride is preferably 300 mg on the administration start date and 150 mg on and after the second administration date.
- the dose is 7-[(3S, 4S) -3- ⁇ (cyclopropylamino) methyl ⁇ -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) It means a value obtained by converting -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride into a free form.
- a pharmaceutically acceptable salt can be used.
- the pharmaceutically acceptable salt include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, maleic acid, fumaric acid, succinic acid, malic acid, malonic acid, methanesulfonic acid, toluene.
- Salts with organic acids such as sulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, acetic acid, trifluoroacetic acid, tartaric acid, or sodium, potassium, magnesium, calcium, aluminum, cesium, chromium, cobalt, copper, iron, zinc, Examples thereof include salts with metals such as platinum and silver. Of these, hydrochloride is particularly preferable. *
- the “free form” means 7-[(3S, 4S) -3- ⁇ (cyclopropylamino) methyl ⁇ -4-fluoropyrrolidine-1 which is neither a salt, a co-crystal nor a hydrate.
- -Yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, the molecular formula is C 21 H 24 F 3 N 3 O 4 is a compound having a molecular weight of 439.44.
- the therapeutic agent of this embodiment is 7-[(3S, 4S) -3- ⁇ (cyclopropylamino) methyl ⁇ -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-Methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof may be constituted alone as an active ingredient.
- the therapeutic agent of this embodiment is 7-[(3S, 4S) -3- ⁇ (cyclopropylamino) methyl ⁇ -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoro Ethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof, other compounds acting as active ingredients and / or pharmaceutically acceptable You may make it comprise as a pharmaceutical composition containing an additive.
- the pharmaceutical composition may contain one or more compounds as other compounds that act as active ingredients and / or pharmaceutically acceptable additives.
- the pharmaceutical composition is, for example, 7-[(3S, 4S) -3- ⁇ (cyclopropylamino) methyl ⁇ -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-Methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof and one or more other compounds and additives that act as active ingredients To be prepared.
- security with respect to aspiration pneumonia, pulmonary abscess, or a lung abscess can be provided.
- an appropriate composition described in the present specification even when a small dose is used, a sufficient therapeutic effect can be obtained while reducing side effects and reducing the appearance frequency of resistant bacteria.
- 150 mg of 150 mg injection is 7-[(3S, 4S) -3- ⁇ (cyclopropylamino) methyl ⁇ -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2- It shows the weight when fluoroethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride is converted to free form.
- Test Examples 1 and 2 are as follows: Clinical evaluation of new antibacterial agents in respiratory infections (2nd edition), JCIA Journal. 2012; 60 (1): 30-45. 9) Based on the judgment criteria, the following criteria were set and judged. The primary endpoint was the effective rate at the end of administration or discontinuation of study drug A.
- the term “at the end of administration” means the evaluation date on the day after the administration of the investigational drug A is completed.
- the time of discontinuation means the evaluation date implemented within 3 days from the last administration date or the discontinuation judgment date of the investigational drug A.
- “when administration is completed or stopped” is expressed as treatment end (EOT, End of Treatment).
- CRP is an abbreviation for C-reactive protein, and is one of the acute phase reactants produced in a short time in response to various inflammations. Bacterial infections such as pneumonia increase in a few hours and decrease rapidly as the inflammation subsides. This is a useful index for observation of therapeutic effects.
- EOT Early efficacy evaluation and end of treatment
- CRP or chest X-ray findings do not change or worsen, and clinical symptoms and body temperature do not change or improve, it is determined that there is no early treatment effect.
- the investigator made an appropriate decision, such as switching to antibiotics. Samples for microbiological evaluation were collected before starting appropriate alternative antimicrobial treatment.
- the discontinuation date is the start date of administration (day 0) or the second day of administration (day 1)
- the determination of early drug efficacy is unnecessary.
- the test result at the time of discontinuation was used.
- the clinical effects at the end of administration or at the time of discontinuation were determined according to Table 1 in three stages: “effective”, “invalid”, and “undecidable”.
- Tables 2 and 3 show the results of early drug efficacy evaluation and treatment completion in Test Examples 1 and 2.
- Tables 4 and 5 show the microbiological effects of Test Examples 1 and 2 according to the causative bacteria.
Abstract
Description
〔1〕7-[(3S,4S)-3-{(シクロプロピルアミノ)メチル}-4-フルオロピロリジン-1-イル]-6-フルオロ-1-(2-フルオロエチル)-8-メトキシ-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸または薬学的に許容されるその塩を有効成分として含有する誤嚥性肺炎、肺化膿症又は肺膿瘍の治療剤。
〔2〕7-[(3S,4S)-3-{(シクロプロピルアミノ)メチル}-4-フルオロピロリジン-1-イル]-6-フルオロ-1-(2-フルオロエチル)-8-メトキシ-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸または薬学的に許容されるその塩を有効成分として含有する誤嚥性肺炎の治療剤。
〔3〕7-[(3S,4S)-3-{(シクロプロピルアミノ)メチル}-4-フルオロピロリジン-1-イル]-6-フルオロ-1-(2-フルオロエチル)-8-メトキシ-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸または薬学的に許容されるその塩を有効成分として含有する肺化膿症又は肺膿瘍の治療剤。
〔4〕前記誤嚥性肺炎、肺化膿症又は肺膿瘍の起因菌が、プレボテラ属に属する菌、ペプトストレプトコッカス属に属する菌、パルビモナス属に属する菌、ペプトニフィラス属に属する菌、ファインゴルディア属に属する菌及び、フソバクテリウム属に属する菌、からなる群から選ばれる1種または2種以上の菌である、〔1〕に記載の治療剤。
〔5〕前記誤嚥性肺炎の起因菌が、プレボテラ属に属する菌、ペプトストレプトコッカス属に属する菌、パルビモナス属に属する菌、ペプトニフィラス属に属する菌、ファインゴルディア属に属する菌及び、フソバクテリウム属に属する菌、からなる群から選ばれる1種または2種以上の菌である、〔2〕に記載の治療剤。
〔6〕前記肺化膿症又は肺膿瘍の起因菌が、プレボテラ属に属する菌、ペプトストレプトコッカス属に属する菌、パルビモナス属に属する菌、ペプトニフィラス属に属する菌、ファインゴルディア属に属する菌及び、フソバクテリウム属に属する菌、からなる群から選ばれる1種または2種以上の菌である、〔3〕に記載の治療剤。
〔7〕前記誤嚥性肺炎、肺化膿症又は肺膿瘍の起因菌が、バクテロイデス属に属する菌、プレボテラ属に属する菌、ポルフィロモナス属に属する菌、フソバクテリウム属に属する菌、レプトトリキア属に属する菌、ペプトストレプトコッカス属に属する菌、パルビモナス属に属する菌、ベイヨネラ属に属する菌、ティシエレラ属に属する菌、ストレプトコッカス・アンギノーサスグループ、及びアクチノマイセス属に属する菌からなる群から選ばれる1種または2種以上の菌である、〔1〕に記載の治療剤。
〔8〕前記誤嚥性肺炎の起因菌が、バクテロイデス属に属する菌、プレボテラ属に属する菌、パルビモナス属に属する菌、ベイヨネラ属に属する菌及びアクチノマイセス属からなる群から選ばれる1種または2種以上の菌である、〔2〕に記載の治療剤。
〔9〕前記肺化膿症又は肺膿瘍の起因菌が、バクテロイデス属に属する菌、プレボテラ属に属する菌、ポルフィロモナス属に属する菌、フソバクテリウム属に属する菌、レプトトリキア属に属する菌、ペプトストレプトコッカス属に属する菌、パルビモナス属に属する菌、ベイヨネラ属に属する菌、ティシエレラ属に属する菌、及びストレプトコッカス・アンギノーサスグループからなる群から選ばれる1種または2種以上の菌である、〔3〕に記載の治療剤。
〔10〕7-[(3S,4S)-3-{(シクロプロピルアミノ)メチル}-4-フルオロピロリジン-1-イル]-6-フルオロ-1-(2-フルオロエチル)-8-メトキシ-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸または薬学的に許容されるその塩の1日あたりの投与量が、7-[(3S,4S)-3-{(シクロプロピルアミノ)メチル}-4-フルオロピロリジン-1-イル]-6-フルオロ-1-(2-フルオロエチル)-8-メトキシ-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸に換算して、投与開始日が300mgであり、投与2日目以降は150mgである、〔1〕に記載の治療剤。
〔11〕7-[(3S,4S)-3-{(シクロプロピルアミノ)メチル}-4-フルオロピロリジン-1-イル]-6-フルオロ-1-(2-フルオロエチル)-8-メトキシ-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸または薬学的に許容されるその塩の1日あたりの投与量が、7-[(3S,4S)-3-{(シクロプロピルアミノ)メチル}-4-フルオロピロリジン-1-イル]-6-フルオロ-1-(2-フルオロエチル)-8-メトキシ-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸に換算して、投与開始日が300mgであり、投与2日目以降は150mgである、〔2〕に記載の治療剤。
〔12〕7-[(3S,4S)-3-{(シクロプロピルアミノ)メチル}-4-フルオロピロリジン-1-イル]-6-フルオロ-1-(2-フルオロエチル)-8-メトキシ-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸または薬学的に許容されるその塩の1日あたりの投与量が、7-[(3S,4S)-3-{(シクロプロピルアミノ)メチル}-4-フルオロピロリジン-1-イル]-6-フルオロ-1-(2-フルオロエチル)-8-メトキシ-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸に換算して、投与開始日が300mgであり、投与2日目以降は150mgである、〔3〕に記載の治療剤。 The gist of the present invention is as follows.
[1] 7-[(3S, 4S) -3-{(cyclopropylamino) methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy- A therapeutic agent for aspiration pneumonia, pulmonary abscess or lung abscess containing 4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
[2] 7-[(3S, 4S) -3-{(cyclopropylamino) methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy- A therapeutic agent for aspiration pneumonia containing 4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
[3] 7-[(3S, 4S) -3-{(cyclopropylamino) methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy- A therapeutic agent for pulmonary abscess or lung abscess comprising 4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
[4] The causative bacteria of the aspiration pneumonia, pulmonary abscess or lung abscess are bacteria belonging to the genus Prevotella, bacteria belonging to the genus Peptostreptococcus, bacteria belonging to the genus Parvimonas, bacteria belonging to the genus Peptoniphyllus, genus Finegordia [1] The therapeutic agent according to [1], which is one type or two or more types of bacteria selected from the group consisting of bacteria belonging to genus and bacteria belonging to the genus Fusobacterium.
[5] The bacteria causing the aspiration pneumonia are bacteria belonging to the genus Prebotella, bacteria belonging to the genus Peptostreptococcus, bacteria belonging to the genus Parvimonas, bacteria belonging to the genus Peptoniphyrus, bacteria belonging to the genus Finegordia, and Fusobacterium genus The therapeutic agent according to [2], which is one or more bacteria selected from the group consisting of bacteria belonging to.
[6] The pathogenic bacteria of the pulmonary abscess or lung abscess are bacteria belonging to the genus Prebotella, bacteria belonging to the genus Peptostreptococcus, bacteria belonging to the genus Parvimonas, bacteria belonging to the genus Peptoniphyrus, bacteria belonging to the genus Finegordia, and The therapeutic agent according to [3], which is one or more bacteria selected from the group consisting of bacteria belonging to the genus Fusobacterium.
[7] The bacteria causing aspiration pneumonia, pulmonary abscess or lung abscess belong to a bacterium belonging to the genus Bacteroides, a bacterium belonging to the genus Prevotella, a bacterium belonging to the genus Porphyromonas, a bacterium belonging to the genus Fusobacterium, or the genus Leptotricia One species selected from the group consisting of a bacterium, a bacterium belonging to the genus Peptostreptococcus, a bacterium belonging to the genus Parvimonas, a bacterium belonging to the genus Bayonella, a bacterium belonging to the genus Tiescherella, a Streptococcus anginasus group, and a bacterium belonging to the genus Actinomyces Alternatively, the therapeutic agent according to [1], which is two or more types of bacteria.
[8] The pathogenic bacterium of the aspiration pneumonia is selected from the group consisting of a bacterium belonging to the genus Bacteroides, a bacterium belonging to the genus Prebotella, a bacterium belonging to the genus Parvimonas, a bacterium belonging to the genus Bayonella and the genus Actinomyces, The therapeutic agent according to [2], which is two or more kinds of bacteria.
[9] The pulmonary abscess or pulmonary abscess causing bacteria are bacteria belonging to the genus Bacteroides, bacteria belonging to the genus Prebotella, bacteria belonging to the genus Porphyromonas, bacteria belonging to the genus Fusobacterium, bacteria belonging to the genus Leptotricia, peptostreptococcus [3] which is one or more bacteria selected from the group consisting of a bacterium belonging to the genus, a bacterium belonging to the genus Parvimonas, a bacterium belonging to the genus Bayonella, a bacterium belonging to the genus Tisierella, and a Streptococcus anginasus group, The therapeutic agent described.
[10] 7-[(3S, 4S) -3-{(cyclopropylamino) methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy- The daily dose of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof is 7-[(3S, 4S) -3-{(cyclopropylamino) Methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, The therapeutic agent according to [1], wherein the administration start date is 300 mg, and 150 mg is administered on and after the second day of administration.
[11] 7-[(3S, 4S) -3-{(cyclopropylamino) methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy- The daily dose of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof is 7-[(3S, 4S) -3-{(cyclopropylamino) Methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, The therapeutic agent according to [2], wherein the administration start date is 300 mg, and the dose is 150 mg after the second day of administration.
[12] 7-[(3S, 4S) -3-{(cyclopropylamino) methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy- The daily dose of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof is 7-[(3S, 4S) -3-{(cyclopropylamino) Methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, The therapeutic agent according to [3], wherein the administration start date is 300 mg, and the dose is 150 mg after the second administration day.
本実施形態の治療剤は、呼吸器疾患の治療剤に関するが、特に呼吸器感染症の治療剤に関する。より具体的には、本実施形態の治療剤は、7-[(3S,4S)-3-{(シクロプロピルアミノ)メチル}-4-フルオロピロリジン-1-イル]-6-フルオロ-1-(2-フルオロエチル)-8-メトキシ-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸または薬学的に許容されるその塩を、ヒトを含む患者に投与することを含む、誤嚥性肺炎、肺化膿症又は肺膿瘍の治療剤に関する。 Hereinafter, one embodiment of the present invention will be described in detail.
The therapeutic agent of this embodiment relates to a therapeutic agent for respiratory diseases, but particularly relates to a therapeutic agent for respiratory infections. More specifically, the therapeutic agent of this embodiment is 7-[(3S, 4S) -3-{(cyclopropylamino) methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- Aspiration comprising administering (2-fluoroethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof to a patient, including a human. The present invention relates to a therapeutic agent for pneumonia, pulmonary abscess or lung abscess.
本明細書における、「誤嚥性肺炎」とは、肺や大気道の腫れや感染を含む呼吸状態であり、有害物質を吸い込むことで引き起こされると考えられている。誤嚥性肺炎に罹患した患者には、咳や呼吸困難といった症状が出ることがある。
本明細書において、誤嚥性肺炎の患者とは、下記の基準を満たす者を意味する。
・胸部X線またはCT画像上に急性に出現した明らかな浸潤影を認める。
・明らかな誤嚥が確認されている、むせの反復が確認されている、嚥下機能評価試験での機能障害が確認されている、または、嚥下機能障害の可能性をもつ疾患の合併もしくは既往歴を有する。
・誤嚥性肺炎に特徴的な症状、炎症所見を示す。
なお、誤嚥性肺炎に特徴的な症状、炎症所見とは、咳嗽、膿性痰、湿性ラ音、呼吸困難、発熱、CRP陽性、白血球増加、低酸素血症等である。 A respiratory infection refers to an infection that occurs at any site in the respiratory tract. The respiratory organ is a general term for organs related to respiration, and refers to organs from the nasal vestibule to the alveoli via the nasal cavity, pharynx, larynx, trachea, bronchi, and bronchioles.
As used herein, “aspiration pneumonia” is a respiratory condition including swelling and infection of the lungs and airways, and is considered to be caused by inhaling harmful substances. Patients with aspiration pneumonia may have symptoms such as coughing and dyspnea.
In this specification, a patient with aspiration pneumonia means a person who satisfies the following criteria.
・ A clear infiltrative shadow that appeared acutely on chest X-rays or CT images is observed.
・ A clear aspiration has been confirmed, repetition of bugs has been confirmed, dysfunction in the swallowing function evaluation test has been confirmed, or a complication or history of a disease with the possibility of swallowing dysfunction Have
-Symptoms and inflammation that are characteristic of aspiration pneumonia.
Symptoms and inflammation that are characteristic of aspiration pneumonia include cough, purulent sputum, moist rales, dyspnea, fever, CRP positive, leukocytosis, hypoxemia and the like.
本明細書において、肺化膿症の患者とは、下記の基準を満たす者を意味する。
・胸部X線またはCT画像上、塊状影または内部に空洞を伴う陰影(結節影、腫瘤影)を認める。(膿の貯留による鏡面像の有無は問わない。)
・肺化膿症・肺膿瘍に特徴的な症状、炎症所見を示す。
なお、肺化膿症又は肺膿瘍に特徴的な症状、炎症所見とは、咳嗽、膿性痰、湿性ラ音、呼吸困難、発熱、CRP陽性、白血球増加、低酸素血症等である。 As used herein, “pulmonary abscess” is a necrotizing pulmonary infection which is also called a lung abscess and is thought to be caused by inhalation of bacteria in the mouth and throat into the lungs. Patients with pulmonary abscess may have symptoms such as fatigue, loss of appetite, night sweats, fever, weight loss, and cough with sputum.
In the present specification, a patient with pulmonary abscess means a person who satisfies the following criteria.
・ On chest X-rays or CT images, massive shadows or shadows with cavities inside (nodular shadows, tumor shadows) are observed. (It does not matter if there is a mirror image due to pus accumulation.)
-Symptoms and inflammation that are characteristic of pulmonary abscess and lung abscess.
Symptoms and inflammation that are characteristic of pulmonary abscess or lung abscess include cough, purulent sputum, moist rales, dyspnea, fever, CRP positive, leukocytosis, hypoxemia and the like.
しかし、出願人は7-[(3S,4S)-3-{(シクロプロピルアミノ)メチル}-4-フルオロピロリジン-1-イル]-6-フルオロ-1-(2-フルオロエチル)-8-メトキシ-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸および薬学的に許容されるその塩が、嫌気性の病原菌に対し有効であり、誤嚥性肺炎の治療に対して効果的であることを見出した。 Finding safe and effective compounds against anaerobic pathogens is important to effectively treat diseases such as aspiration pneumonia, pulmonary abscess or lung abscess. Applicant is 7-[(3S, 4S) -3-{(cyclopropylamino) methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy- It has been found that 4-oxo-1,4-dihydroquinoline-3-carboxylic acid and pharmaceutically acceptable salts thereof are effective against anaerobic pathogens, unlike other quinolone compounds. For example, an injection of a quinolone compound such as levofloxacin, ciprofloxacin or pazufloxacin is considered not suitable as a therapeutic agent for aspiration pneumonia (Non-patent Document 2).
However, the applicant is not able to use 7-[(3S, 4S) -3-{(cyclopropylamino) methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8- Methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and pharmaceutically acceptable salts thereof are effective against anaerobic pathogens and effective in the treatment of aspiration pneumonia I found out.
誤嚥性肺炎、肺化膿症又は肺膿瘍の起因菌となる偏性嫌気性菌として、バクテロイデス属(Bacteroides属)に属する菌、プレボテラ属(Prevotella属)に属する菌、ポルフィロモナス属(Porphyromonas属)に属する菌、フソバクテリウム属(Fusobacterium属)に属する菌、レプトトリキア属(Leptotrichia属)に属する菌、ペプトストレプトコッカス属(Peptostreptococcus属)に属する菌、パルビモナス属(Parvimonas属)に属する菌等、ベイヨネラ属(Veillonella属)に属する菌、ティシエレラ属(Tissierella属)に属する菌、ペプトニフィラス属(Peptonitphilus属)に属する菌、及びファインゴルディア属(Finegoldia属)に属する菌、通性嫌気性菌としてストレプトコッカス属に含まれるストレプトコッカス・アンギノーサスグループ(Streptococcus Anginosus group)、アクチノマイセス属(Actinomyces属)に属する菌等が挙げられる。7-[(3S,4S)-3-{(シクロプロピルアミノ)メチル}-4-フルオロピロリジン-1-イル]-6-フルオロ-1-(2-フルオロエチル)-8-メトキシ-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸は、前述の嫌気性菌に対して高い抗菌力を発揮し、誤嚥性肺炎、肺化膿症又は肺膿瘍に対し、高い治療効果を示す。 7-[(3S, 4S) -3-{(cyclopropylamino) methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4 -Oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof can be produced, for example, according to the method described in Patent Document 1 or 2.
As an obligate anaerobe that causes aspiration pneumonia, pulmonary abscess or lung abscess, bacteria belonging to the genus Bacteroides (genus Bacteroides), bacteria belonging to the genus Prevotella (genus Prevotella), genus Porphyromonas (genus Porphyromonas) ), Bacteria belonging to the genus Fusobacterium (genus Fusobacterium), bacteria belonging to the genus Leptotrichia (genus Leptotrichia), bacteria belonging to the genus Peptostreptococcus (genus Peptostreptococcus), bacteria belonging to the genus Parvimonas (genus Parvimonas), genus Bayonella (Veillonella), bacteria belonging to the genus Tissierella (genus Tissierella), bacteria belonging to the genus Peptonitphilus (genus Peptonitphilus), bacteria belonging to the genus Finegoldia (genus Finegoldia), Streptococcus as facultative anaerobes Included Streptococcus Anginosus group, Actino Bacteria such as belonging to Isis genus (Actinomyces genus) can be mentioned. 7-[(3S, 4S) -3-{(cyclopropylamino) methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo 1,4-dihydroquinoline-3-carboxylic acid exhibits high antibacterial activity against the above-mentioned anaerobic bacteria and exhibits a high therapeutic effect against aspiration pneumonia, pulmonary abscess or lung abscess.
誤嚥性肺炎の治療に関しては、特に、誤嚥性肺炎の起因菌が、バクテロイデス属に属する菌、プレボテラ属に属する菌、パルビモナス属に属する菌、ベイヨネラ属に属する菌、又はアクチノマイセス属に属する菌である場合、7-[(3S,4S)-3-{(シクロプロピルアミノ)メチル}-4-フルオロピロリジン-1-イル]-6-フルオロ-1-(2-フルオロエチル)-8-メトキシ-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸の高い治療効果が発揮される。 Examples of bacteria that cause aspiration pneumonia include bacteria belonging to the genus Prevotella (genus Prevotella), bacteria belonging to the genus Peptostreptococcus (genus Peptostreptococcus), bacteria belonging to the genus Parvimonas (genus Parvimonas), and the genus Peptonifilus (genus Peptonitphilus) Examples include bacteria belonging to the genus Finegoldia, bacteria belonging to the genus Fusobacterium, bacteria belonging to the genus Bacteroides, bacteria belonging to the genus Streptococcus, and the like.
Regarding the treatment of aspiration pneumonia, in particular, the causative bacteria of aspiration pneumonia are the bacteria belonging to the genus Bacteroides, the bacteria belonging to the genus Prevotella, the bacteria belonging to the genus Parvimonas, the bacteria belonging to the genus Bayonella, or the genus Actinomyces. 7-[(3S, 4S) -3-{(cyclopropylamino) methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8 The high therapeutic effect of -methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid is exerted.
ペプトストレプトコッカス属に属する菌として、例えば、P.anaerobius、又はP.stomatisが挙げられる。 Examples of bacteria belonging to the genus Prebotella include, for example, P. denticola, P. loescheii, P. melaninogenica, P. intermedia, P. nigrescens, P. pallens, P. buccae, P. oris, P. buccalis, P. oralis, P. Bivia, P. disiens, P. pleuritidis, P. bergensis, P. timonensis, or P. nanceiencis genus. 7-[(3S, 4S) -3-{(cyclopropylamino) methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo From the viewpoint of the therapeutic effect of 1,4-dihydroquinoline-3-carboxylic acid, more preferably, when the causative organism of aspiration pneumonia is P. melaninogenica, P. intermedia, or P. buccae, pulmonary abscess And the pathogen causing pulmonary abscess may be P. melaninogenica, P. intermedia, or P. oralis.
Examples of bacteria belonging to the genus Peptostreptococcus include P. anaerobius or P. stomatis.
ペプトニフィラス属に属する菌として、例えば、Peptoniphilus asaccharolyticus、Peptoniphilus ivorii、Peptoniphilus lacrimalis又はPeptoniphilus hareiが挙げられる。7-[(3S,4S)-3-{(シクロプロピルアミノ)メチル}-4-フルオロピロリジン-1-イル]-6-フルオロ-1-(2-フルオロエチル)-8-メトキシ-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸の治療効果という観点から、より好ましくは、誤嚥性肺炎、肺化膿症又は肺膿瘍の起因菌が、Peptoniphilus asaccharolyticusである場合が挙げられる。 Examples of bacteria belonging to the genus Parvimonas include P. micra. 7-[(3S, 4S) -3-{(cyclopropylamino) methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo More preferably, from the viewpoint of the therapeutic effect of 1,4-dihydroquinoline-3-carboxylic acid, the cause of aspiration pneumonia, pulmonary abscess or lung abscess is P. micra.
Examples of bacteria belonging to the genus Peptoniphilus include Peptoniphilus asaccharolyticus, Peptoniphilus ivorii, Peptoniphilus lacrimalis, or Peptoniphilus harei. 7-[(3S, 4S) -3-{(cyclopropylamino) methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo More preferably, from the viewpoint of the therapeutic effect of 1,4-dihydroquinoline-3-carboxylic acid, the cause of aspiration pneumonia, pulmonary abscess or lung abscess is Peptoniphilus asaccharolyticus.
バクテロイデス属に属する菌として、例えば、B. fragilis、B. thetaiotaomicron、B. vulgatus、B. ovatus、B. uniformis、B. eggerthii、B. nordii、B. salyersae、又はB. massiliensisが挙げられる。7-[(3S,4S)-3-{(シクロプロピルアミノ)メチル}-4-フルオロピロリジン-1-イル]-6-フルオロ-1-(2-フルオロエチル)-8-メトキシ-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸の治療効果という観点から、より好ましくは、肺化膿症又は肺膿瘍の起因菌がB. fragilisである場合が挙げられる。 Examples of the bacteria belonging to the genus Fusobacterium include F. necrophorum, F. nucleatum, F. mortiferum, and F. varium. 7-[(3S, 4S) -3-{(cyclopropylamino) methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo From the viewpoint of the therapeutic effect of 1,4-dihydroquinoline-3-carboxylic acid, more preferably, the cause of pulmonary abscess or lung abscess is F. nucleatum or F. necrophorum.
Examples of the bacteria belonging to the genus Bacteroides include B. fragilis, B. thetaiotaomicron, B. vulgatus, B. ovatus, B. uniformis, B. eggerthii, B. nordii, B. salyersae, or B. massiliensis. 7-[(3S, 4S) -3-{(cyclopropylamino) methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo From the viewpoint of the therapeutic effect of 1,4-dihydroquinoline-3-carboxylic acid, more preferably, B. fragilis is the causative agent of pulmonary abscess or lung abscess.
ベイヨネラ属に属する菌として、例えば、V. parvula、V. atypica、又はV. montpelliensisが挙げられる。 Examples of bacteria belonging to the genus Leptotricia include L. buccalis, L. hofstadii, L. hongkongensis, L. shahii, L. goodfellowii, L. trevisanii, or L. wadei. 7-[(3S, 4S) -3-{(cyclopropylamino) methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo From the viewpoint of the therapeutic effect of 1,4-dihydroquinoline-3-carboxylic acid, more preferably, the cause of pulmonary abscess or lung abscess is L. buccalis.
Examples of the bacteria belonging to the genus Bayonella include V. parvula, V. atypica, and V. montpelliensis.
(実施例) As mentioned above, according to this embodiment, the technique regarding the therapeutic agent which has a high therapeutic effect and safety | security with respect to aspiration pneumonia, pulmonary abscess, or a lung abscess can be provided. By using an appropriate composition described in the present specification, even when a small dose is used, a sufficient therapeutic effect can be obtained while reducing side effects and reducing the appearance frequency of resistant bacteria.
(Example)
国際公開第2016/195014号に開示されている方法に準じて、7-[(3S,4S)-3-{(シクロプロピルアミノ)メチル}-4-フルオロピロリジン-1-イル]-6-フルオロ-1-(2-フルオロエチル)-8-メトキシ-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸の150mg注射剤(以下、治験薬Aとも記載する)を製造した。 The present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited by these examples.
According to the method disclosed in WO2016 / 195014, 7-[(3S, 4S) -3-{(cyclopropylamino) methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro A 150 mg injection of -1- (2-fluoroethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (hereinafter also referred to as study drug A) was prepared.
(試験例1)誤嚥性肺炎
治験薬Aを、下記の基準を満たす誤嚥性肺炎を疑われる被験者13例に対し、7日間~14日間点滴静脈内投与した。
・16歳以上で投与開始前48時間以内に撮影された胸部X線またはCT画像上に急性に出現した明らかな浸潤影を認める。
・明らかな誤嚥が確認、むせや嚥下機能障害、嚥下機能障害の可能性をもつ疾患を有しているまたは既往歴を有する。
・誤嚥性肺炎に特徴的な症状、炎症所見を示す。
投与開始1日目は治験薬Aを2本(300mg/日)、投与2日目は治験薬Aを1本(150mg/日)用い、その後同投与量(150mg/日)を維持した。注射剤の投与は1本あたり約1時間かけて点滴静脈内投与を行った。
(試験例2)肺化膿症又は肺膿瘍
治験薬Aを、下記の基準を満たす肺化膿症又は肺膿瘍を疑われる披験者11例に対し、7日間~14日間点滴静脈内投与した。
・16歳以上で、投与開始前48時間以内に撮影された胸部X線またはCT画像上、塊状影または内部に空洞を伴う陰影(結節影、腫瘤影)を認める。なお、膿の貯留による鏡面像の有無は問わない。
・肺化膿症・肺膿瘍に特徴的な症状、炎症所見を示す。
投与開始1日目は治験薬Aを2本(300mg/日)、投与2日目は治験薬Aを1本(150mg/日)用い、その後同投与量(150mg/日)を維持した。注射剤の投与は1本あたり約1時間かけて点滴静脈内投与を行った。
試験例1、2の臨床効果は、呼吸器感染症における新規抗菌薬の臨床評価法(第二版)、日化療会誌. 2012; 60(1): 30-45. 9 )の肺炎の臨床効果判定基準を基に、下記の基準を設定し、判定を行なった。なお、主要評価項目は、治験薬Aの投与終了時又は中止時の有効率とした。 Note that “150 mg” of 150 mg injection is 7-[(3S, 4S) -3-{(cyclopropylamino) methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2- It shows the weight when fluoroethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride is converted to free form. When producing an injection, 7-[(3S, 4S) -3-{(cyclopropylamino) methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) Use is made of 162.5 mg (converted to free form: 150 mg) of -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride.
(Test Example 1) Aspiration pneumonia Study drug A was administered intravenously for 7 to 14 days to 13 subjects suspected of having aspiration pneumonia meeting the following criteria.
・ A clear infiltration shadow appears acutely on chest X-rays or CT images taken within 48 hours before the start of administration at the age of 16 years or older.
・ Confirmation of clear aspiration, disease or dysphagia, potential dysphagia, or history.
-Symptoms and inflammation that are characteristic of aspiration pneumonia.
On the first day of administration, two investigational drugs A (300 mg / day) were used, and on the second day of administration, one investigational drug A (150 mg / day) was used, and then the same dose (150 mg / day) was maintained. The injection was administered by intravenous infusion over about 1 hour per one.
(Test Example 2) Pulmonary abscess or lung abscess investigational drug A was intravenously administered intravenously for 7 to 14 days to 11 subjects suspected of having pulmonary abscess or lung abscess satisfying the following criteria.
-Chest X-rays or CT images taken within 48 hours prior to the start of administration at the age of 16 years or older, a massive shadow or a shadow with a cavity (nodular shadow, tumor shadow) is observed. In addition, the presence or absence of the specular image by the accumulation of pus does not ask | require.
-Symptoms and inflammation that are characteristic of pulmonary abscess and lung abscess.
On the first day of administration, two investigational drugs A (300 mg / day) were used, and on the second day of administration, one investigational drug A (150 mg / day) was used, and then the same dose (150 mg / day) was maintained. The injection was administered by intravenous infusion over about 1 hour per one.
The clinical effects of Test Examples 1 and 2 are as follows: Clinical evaluation of new antibacterial agents in respiratory infections (2nd edition), JCIA Journal. 2012; 60 (1): 30-45. 9) Based on the judgment criteria, the following criteria were set and judged. The primary endpoint was the effective rate at the end of administration or discontinuation of study drug A.
・早期薬効評価及び治療終了時(EOT)
早期薬効評価は、投与3日後に表1に従い、「早期治療効果あり」「早期治療効果なし」「判定不能」の3段階で判定した。
「早期治療効果あり」の定義は、投与3日後に著しい改善を認めた症例(4日後以降の投与終了・継続とは無関係)とした。また、投与開始前に比べて、投与3日後のCRP値や胸部X線が改善していない症例については、CRPや胸部X線所見が不変又は悪化にもかかわらず、臨床症状及び体温の改善がある場合は「早期治療効果あり」と判断した。
CRPや胸部X線所見が不変又は悪化し、臨床症状及び体温が不変又は改善がない場合は、「早期治療効果なし」と判定し、被験者の安全を十分に考慮し、治験を中止し他の抗菌薬投与に切り替えるなど治験責任医師等が適切に判断した。なお、適切な代替の抗菌薬治療を開始する前に、微生物学的評価のための検体を採取した。 In the present specification, the term “at the end of administration” means the evaluation date on the day after the administration of the investigational drug A is completed. Moreover, the time of discontinuation means the evaluation date implemented within 3 days from the last administration date or the discontinuation judgment date of the investigational drug A. Furthermore, “when administration is completed or stopped” is expressed as treatment end (EOT, End of Treatment). CRP is an abbreviation for C-reactive protein, and is one of the acute phase reactants produced in a short time in response to various inflammations. Bacterial infections such as pneumonia increase in a few hours and decrease rapidly as the inflammation subsides. This is a useful index for observation of therapeutic effects.
・ Early efficacy evaluation and end of treatment (EOT)
The early drug efficacy evaluation was determined according to Table 1, 3 days after administration, in three stages: “Early therapeutic effect”, “No early therapeutic effect”, and “Undeterminable”.
The definition of “with early treatment effect” was defined as a case in which significant improvement was observed 3 days after administration (regardless of whether administration was completed or continued after 4 days). In addition, in cases where CRP values and chest X-rays did not improve 3 days after administration compared to before the start of administration, clinical symptoms and body temperature were improved, although CRP and chest X-ray findings were unchanged or worsened. In some cases, it was judged as “early therapeutic effect”.
If CRP or chest X-ray findings do not change or worsen, and clinical symptoms and body temperature do not change or improve, it is determined that there is no early treatment effect. The investigator made an appropriate decision, such as switching to antibiotics. Samples for microbiological evaluation were collected before starting appropriate alternative antimicrobial treatment.
治療終了時(EOT)は、投与終了時又は中止時の臨床効果について、表1に従い、「有効」「無効」「判定不能」の3段階で判定した。投与終了時翌日以降に中止した場合は、投与終了時の臨床効果について判定し、中止時の臨床効果は判定不要とした。
また、中止した場合又は治験薬投与終了後に代替の抗菌薬治療に変更した場合は「無効」と判断した。ただし、治療終了時(EOT)に表1の判定基準に従い「有効」と判断された場合は、代替の抗菌薬治療に変更した場合であっても、この限りではない。なお、代替の抗菌薬治療に変更する場合は、原則変更前に規定の検査、診察及び治療終了時の判定を実施した。 In addition, when the discontinuation date is the start date of administration (day 0) or the second day of administration (day 1), the determination of early drug efficacy is unnecessary. In the case of the 3rd day after administration (2nd day) or later, the test result at the time of discontinuation was used.
At the end of treatment (EOT), the clinical effects at the end of administration or at the time of discontinuation were determined according to Table 1 in three stages: “effective”, “invalid”, and “undecidable”. When the treatment was discontinued after the next day after the end of the administration, the clinical effect at the end of the administration was determined, and the clinical effect at the time of the discontinuation was unnecessary.
In addition, it was judged as “invalid” when it was discontinued or when it was changed to an alternative antibacterial treatment after the end of study drug administration. However, this does not apply to cases where it is determined to be “effective” at the end of treatment (EOT) in accordance with the criteria shown in Table 1, even if it is changed to alternative antimicrobial treatment. In addition, when changing to an alternative antibacterial treatment, prescribed tests, examinations and judgments at the end of treatment were conducted before the principle change.
有効率=(「有効」と判定された被験者数÷「有効」又は「無効」と判定された被験者数)×100 (%) The effective rate is a value obtained by the following formula.
Effective rate = (number of subjects judged “valid” ÷ number of subjects judged “valid” or “invalid”) × 100 (%)
Claims (12)
- 7-[(3S,4S)-3-{(シクロプロピルアミノ)メチル}-4-フルオロピロリジン-1-イル]-6-フルオロ-1-(2-フルオロエチル)-8-メトキシ-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸または薬学的に許容されるその塩を有効成分として含有する誤嚥性肺炎、肺化膿症又は肺膿瘍の治療剤。 7-[(3S, 4S) -3-{(cyclopropylamino) methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo A therapeutic agent for aspiration pneumonia, pulmonary abscess or lung abscess containing 1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
- 7-[(3S,4S)-3-{(シクロプロピルアミノ)メチル}-4-フルオロピロリジン-1-イル]-6-フルオロ-1-(2-フルオロエチル)-8-メトキシ-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸または薬学的に許容されるその塩を有効成分として含有する誤嚥性肺炎の治療剤。 7-[(3S, 4S) -3-{(cyclopropylamino) methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo A therapeutic agent for aspiration pneumonia containing 1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
- 7-[(3S,4S)-3-{(シクロプロピルアミノ)メチル}-4-フルオロピロリジン-1-イル]-6-フルオロ-1-(2-フルオロエチル)-8-メトキシ-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸または薬学的に許容されるその塩を有効成分として含有する肺化膿症又は肺膿瘍の治療剤。 7-[(3S, 4S) -3-{(cyclopropylamino) methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo A therapeutic agent for pulmonary abscess or lung abscess comprising 1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof as an active ingredient.
- 前記誤嚥性肺炎、肺化膿症又は肺膿瘍の起因菌が、プレボテラ属に属する菌、ペプトストレプトコッカス属に属する菌、パルビモナス属に属する菌、ペプトニフィラス属に属する菌、ファインゴルディア属に属する菌及び、フソバクテリウム属に属する菌、からなる群から選ばれる1種または2種以上の菌である、請求項1に記載の治療剤。 Aspiration pneumonia, pulmonary abscess or lung abscess causing bacteria belonging to the genus Prebotella, bacteria belonging to the genus Peptostreptococcus, bacteria belonging to the genus Parvimonas, bacteria belonging to the genus Peptoniphyrus, bacteria belonging to the genus Finegordia The therapeutic agent according to claim 1, which is one or more bacteria selected from the group consisting of bacteria belonging to the genus Fusobacterium.
- 前記誤嚥性肺炎の起因菌が、プレボテラ属に属する菌、ペプトストレプトコッカス属に属する菌、パルビモナス属に属する菌、ペプトニフィラス属に属する菌、ファインゴルディア属に属する菌及び、フソバクテリウム属に属する菌、からなる群から選ばれる1種または2種以上の菌である、請求項2に記載の治療剤。 Bacteria belonging to the genus Prevotella, bacteria belonging to the genus Peptostreptococcus, bacteria belonging to the genus Parvimonas, bacteria belonging to the genus Peptoniphylla, bacteria belonging to the genus Finegordia, and bacteria belonging to the genus Fusobacterium The therapeutic agent according to claim 2, which is one or more bacteria selected from the group consisting of.
- 前記肺化膿症又は肺膿瘍の起因菌が、プレボテラ属に属する菌、ペプトストレプトコッカス属に属する菌、パルビモナス属に属する菌、ペプトニフィラス属に属する菌、ファインゴルディア属に属する菌及び、フソバクテリウム属に属する菌、からなる群から選ばれる1種または2種以上の菌である、請求項3に記載の治療剤。 The pulmonary abscess or pulmonary abscess-causing bacterium is a bacterium belonging to the genus Prebotella, a bacterium belonging to the genus Peptostreptococcus, a bacterium belonging to the genus Parvimonas, a bacterium belonging to the genus Peptoniphyrus, a bacterium belonging to the genus Finegordia, and a genus Fusobacterium. The therapeutic agent of Claim 3 which is 1 type, or 2 or more types of microbe chosen from the group which consists of a microbe to which it belongs.
- 前記誤嚥性肺炎、肺化膿症又は肺膿瘍の起因菌が、バクテロイデス属に属する菌、プレボテラ属に属する菌、ポルフィロモナス属に属する菌、フソバクテリウム属に属する菌、レプトトリキア属に属する菌、ペプトストレプトコッカス属に属する菌、パルビモナス属に属する菌、ベイヨネラ属に属する菌、ティシエレラ属に属する菌、ストレプトコッカス・アンギノーサスグループ、及びアクチノマイセス属に属する菌からなる群から選ばれる1種または2種以上の菌である、請求項1に記載の治療剤。 Bacteria belonging to the genus Bacteroides, bacteria belonging to the genus Prevotella, bacteria belonging to the genus Porphyromonas, bacteria belonging to the genus Fusobacterium, bacteria belonging to the genus Leptotricia, pep One or two species selected from the group consisting of bacteria belonging to the genus Tostreptococcus, bacteria belonging to the genus Parvimonas, bacteria belonging to the genus Bayonella, bacteria belonging to the genus Tissierella, Streptococcus anginosas group, and bacteria belonging to the genus Actinomyces The therapeutic agent of Claim 1 which is the above microbe.
- 前記誤嚥性肺炎の起因菌が、バクテロイデス属に属する菌、プレボテラ属に属する菌、パルビモナス属に属する菌、ベイヨネラ属に属する菌及びアクチノマイセス属からなる群から選ばれる1種または2種以上の菌である、請求項2に記載の治療剤。 One or more kinds selected from the group consisting of bacteria belonging to the genus Bacteroides, bacteria belonging to the genus Prevoterra, bacteria belonging to the genus Parvimonas, bacteria belonging to the genus Bayonella and the genus Actinomyces The therapeutic agent according to claim 2, wherein
- 前記肺化膿症又は肺膿瘍の起因菌が、バクテロイデス属に属する菌、プレボテラ属に属する菌、ポルフィロモナス属に属する菌、フソバクテリウム属に属する菌、レプトトリキア属に属する菌、ペプトストレプトコッカス属に属する菌、パルビモナス属に属する菌、ベイヨネラ属に属する菌、ティシエレラ属に属する菌、及びストレプトコッカス・アンギノーサスグループからなる群から選ばれる1種または2種以上の菌である、請求項3に記載の治療剤。 The pulmonary abscess or pulmonary abscess-causing bacterium belongs to the genus Bacteroides, the bacterium belonging to the genus Prevotella, the bacterium belonging to the genus Porphyromonas, the bacterium belonging to the genus Fusobacterium, the bacterium belonging to the genus Leptotricia, or the genus Peptostreptococcus The treatment according to claim 3, which is one or more bacteria selected from the group consisting of a bacterium, a bacterium belonging to the genus Parvimonas, a bacterium belonging to the genus Bayonella, a bacterium belonging to the genus Tisierella, and a Streptococcus anginosus group. Agent.
- 7-[(3S,4S)-3-{(シクロプロピルアミノ)メチル}-4-フルオロピロリジン-1-イル]-6-フルオロ-1-(2-フルオロエチル)-8-メトキシ-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸または薬学的に許容されるその塩の1日あたりの投与量が、7-[(3S,4S)-3-{(シクロプロピルアミノ)メチル}-4-フルオロピロリジン-1-イル]-6-フルオロ-1-(2-フルオロエチル)-8-メトキシ-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸に換算して、投与開始日が300mgであり、投与2日目以降は150mgである、請求項1に記載の治療剤。 7-[(3S, 4S) -3-{(cyclopropylamino) methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo The daily dose of -1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof is 7-[(3S, 4S) -3-{(cyclopropylamino) methyl}- 4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid in terms of start date of administration Is 300 mg, and the therapeutic agent according to claim 1, which is 150 mg after the second day of administration.
- 7-[(3S,4S)-3-{(シクロプロピルアミノ)メチル}-4-フルオロピロリジン-1-イル]-6-フルオロ-1-(2-フルオロエチル)-8-メトキシ-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸または薬学的に許容されるその塩の1日あたりの投与量が、7-[(3S,4S)-3-{(シクロプロピルアミノ)メチル}-4-フルオロピロリジン-1-イル]-6-フルオロ-1-(2-フルオロエチル)-8-メトキシ-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸に換算して、投与開始日が300mgであり、投与2日目以降は150mgである、請求項2に記載の治療剤。 7-[(3S, 4S) -3-{(cyclopropylamino) methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo The daily dose of -1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof is 7-[(3S, 4S) -3-{(cyclopropylamino) methyl}- 4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid in terms of start date of administration Is 300 mg, and the therapeutic agent according to claim 2, which is 150 mg after the second day of administration.
- 7-[(3S,4S)-3-{(シクロプロピルアミノ)メチル}-4-フルオロピロリジン-1-イル]-6-フルオロ-1-(2-フルオロエチル)-8-メトキシ-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸または薬学的に許容されるその塩の1日あたりの投与量が、7-[(3S,4S)-3-{(シクロプロピルアミノ)メチル}-4-フルオロピロリジン-1-イル]-6-フルオロ-1-(2-フルオロエチル)-8-メトキシ-4-オキソ-1,4-ジヒドロキノリン-3-カルボン酸に換算して、投与開始日が300mgであり、投与2日目以降は150mgである、請求項3に記載の治療剤。
7-[(3S, 4S) -3-{(cyclopropylamino) methyl} -4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo The daily dose of -1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof is 7-[(3S, 4S) -3-{(cyclopropylamino) methyl}- 4-fluoropyrrolidin-1-yl] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid in terms of start date of administration Is 300 mg, and the therapeutic agent according to claim 3, which is 150 mg after the second day of administration.
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EA202090066A EA202090066A1 (en) | 2018-03-30 | 2018-06-15 | THERAPEUTIC FOR THE TREATMENT OF ASPIRATED PNEUMONIA, PULMONARY FORCING OR LUNG ABCESS |
AU2018283234A AU2018283234A1 (en) | 2017-06-16 | 2018-06-15 | Therapeutic agent for aspiration pneumonia, lung suppuration, or lung abscess |
JP2019525551A JP6618660B2 (en) | 2017-06-16 | 2018-06-15 | Treatment for aspiration pneumonia, pulmonary abscess or lung abscess |
US16/620,630 US20210137913A1 (en) | 2017-06-16 | 2018-06-15 | Therapeutic agent for aspiration pneumonia, lung suppuration, or lung abscess |
MX2019014931A MX2019014931A (en) | 2017-06-16 | 2018-06-15 | Therapeutic agent for aspiration pneumonia, lung suppuration, or lung abscess. |
CN202310755318.XA CN116549446A (en) | 2017-06-16 | 2018-06-15 | Therapeutic agent for aspiration pneumonia, lung suppuration or lung abscess |
SG11201911826VA SG11201911826VA (en) | 2017-06-16 | 2018-06-15 | Therapeutic agent for aspiration pneumonia, lung suppuration, or lung abscess |
KR1020207000644A KR20200016960A (en) | 2017-06-16 | 2018-06-15 | Drugs for aspiration pneumonia, pneumonia, or lung abscess |
CN201880039674.9A CN110891571A (en) | 2017-06-16 | 2018-06-15 | Therapeutic agent for aspiration pneumonia, lung suppuration or lung abscess |
CA3067188A CA3067188A1 (en) | 2017-06-16 | 2018-06-15 | Therapeutic agent for aspiration pneumonia, lung suppuration, or lung abscess |
BR112019025960-0A BR112019025960A2 (en) | 2017-06-16 | 2018-06-15 | therapeutic agent for aspiration pneumonia, lung suppuration or lung abscess |
EP18818391.7A EP3639826A4 (en) | 2017-06-16 | 2018-06-15 | Therapeutic agent for aspiration pneumonia, lung suppuration, or lung abscess |
IL270831A IL270831A (en) | 2017-06-16 | 2019-11-21 | Therapeutic agent for aspiration pneumonia, lung suppuration, or lung abscess |
PH12019502835A PH12019502835A1 (en) | 2017-06-16 | 2019-12-16 | Therapeutic agent for aspiration pneumonia, lung suppuration, or lung abscess |
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