Therapeutic agent for inhalation pneumonia, pulmonary suppuration or pulmonary abscess

Abstract

The present invention is a therapeutic agent for inhalation pneumonia, pulmonary suppuration or pulmonary abscess. [Problem] The present invention relates to a safer and more effective therapeutic agent for respiratory tract infections. [Solution] A therapeutic agent for inhalation pneumonia, pulmonary suppuration or pulmonary abscess, said agent containing, as an active ingredient, 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.

Description

[0001] This application is a divisional application of application number "201880039674.9" entitled "Therapeutic agent for aspiration pneumonia, pulmonary suppuration or pulmonary abscess". Technical Field

[0002] This invention relates to therapeutic agents for aspiration pneumonia, lung suppuration, or lung abscess. Background Technology

[0003] Since the development of norfloxacin, quinolone carboxylic acid antibacterial agents known as new quinolones have been developed worldwide, and many of these new quinolone antibacterial agents are now widely used as treatments for infectious diseases.

[0004] Meanwhile, the applicant has already disclosed quinolone carboxylic acid derivatives represented by general formula (1) (Patent Document 1).

[0005] [Formula 1]

[0006]

[0007] In equation (1), R 1 Represents an alkyl group having 1 to 6 carbon atoms, optionally substituted with one or more halogen atoms; a cycloalkyl group having 3 to 6 carbon atoms, optionally substituted with one or more halogen atoms; or an aryl or heteroaryl group, optionally substituted with one or more identical or different substituents selected from halogen atoms and amino groups; R 2 Represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a pharmaceutically acceptable cation; R 3 Represents a hydrogen atom, halogen atom, hydroxyl group, amino group, or alkyl group having 1 to 3 carbon atoms; R 4 Represents a hydrogen atom or a halogen atom; R 5 Represents a fluorine atom; R 6 Represents a hydrogen atom or a fluorine atom; and A represents a nitrogen atom or =CX (where X represents a hydrogen atom, a halogen atom, an amino group, a cyano group, or an alkyl group having 1 to 3 carbon atoms optionally substituted with one or more halogen atoms, or an alkoxy group having 1 to 3 carbon atoms optionally substituted with one or more halogen atoms).

[0008] Additionally, Patent Document 1 discloses 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as one of the quinolone carboxylic acid derivatives described above. Furthermore, its hydrochloride salt is disclosed in Patent Document 2.

[0009] Another example of respiratory infection is aspiration pneumonia. Aspiration pneumonia accounts for a large proportion of pneumonia in the elderly and is a serious, refractory, recurrent, and highly fatal disease (Non-Patent Literature 1). Pathogens of aspiration pneumonia include anaerobic bacteria, Staphylococcus aureus, and enterobacteria (Non-Patent Literature 1), but no effective treatment for aspiration pneumonia has yet been established. Currently available quinolone formulations include levofloxacin, ciprofloxacin, pazufloxacin, moxifloxacin, sitafloxacin, and canofloxacin. For aspiration pneumonia (a highly serious disease), most initial treatments use injectable formulations; however, among the aforementioned quinolone formulations, levofloxacin, ciprofloxacin, and pazufloxacin, for which injectable formulations are available, have insufficient antibacterial activity against anaerobic bacteria and are not recommended for use in patients suspected of having aspiration pneumonia (Non-Patent Literature 2). Among oral formulations, sitafloxacin, moxifloxacin, and canofloxacin may be effective against anaerobic bacterial infections (Non-Patent Literature 3 to 5), but there are no papers reporting strong evidence for their use against aspiration pneumonia, and no effective treatment has yet been established.

[0010] Similar to aspiration pneumonia, examples of respiratory infections primarily caused by anaerobic bacteria include lung abscess (Non-Patent Literature 6). Although there are reports of observed therapeutic efficacy for moxifloxacin and pazufloxacin (Non-Patent Literature 3-4 and Non-Patent Literature 7), they have not yet been established as effective treatments.

[0011] Citation List

[0012] Non-patent literature

[0013] Non-patent document 1: Journal of the Japanese Society of Internal Medicine, No. 99-11, November 10, 2010, pp. 2746-2751.

[0014] Non-patent document 2: Japan Respiratory Society, "Medical and Nursing Care-Related Pneumonia Diagnosis and Treatment Clinic", page 23.

[0015] Non-patent literature 3: Infection (Munich, Germany) (2008), 36(1), 23-30.

[0016] Non-patent literature 4: Expert Review of Respiratory Medicine (2007), 1(1), 111-119.

[0017] Non-patent literature 5: Japan Respiratory Society, 'Adult Pneumonia Diagnosis and Treatment Guideline 2017', page 24.

[0018] Non-patent document 6: Journal of the Japanese Respiratory Society, 49(9): 623-628, 2011.

[0019] Non-patent document 7: Nippon Kagaku Ryoho Gakkai Zasshi (1999), 47 (Supplement 1), 196-203.

[0020] Patent documents

[0021] Patent Document 1: International Publication No. WO 2005 / 026147

[0022] Patent Document 2: International Publication No. WO 2013 / 069297 Invention Overview

[0023] Technical issues

[0024] The purpose of this invention is to provide a novel therapeutic agent for respiratory tract infections.

[0025] Solution to the problem

[0026] The inventors have investigated highly effective and safe therapeutic agents for respiratory infections. They have conducted extensive research on the aforementioned problems and discovered that 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid is extremely effective as a therapeutic agent for aspiration pneumonia, pulmonary suppuration, or lung abscess, and thus completed this invention.

[0027] The gist of this invention is as follows:

[0028] [1] A treatment for aspiration pneumonia, lung suppuration or lung abscess, comprising 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof as the active ingredient.

[0029] [2] A treatment for aspiration pneumonia, comprising 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof as the active ingredient.

[0030] [3] A therapeutic agent for lung suppuration or lung abscess, comprising 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof as the active ingredient.

[0031] [4] According to the therapeutic agent described in [1], the pathogen causing aspiration pneumonia, pulmonary suppuration or pulmonary abscess is selected from one or more of the following bacteria: bacteria belonging to the genus Prevotella, bacteria belonging to the genus Peptostreptococcus, bacteria belonging to the genus Parvimonas, bacteria belonging to the genus Peptoniphilus, bacteria belonging to the genus Finegoldia and bacteria belonging to the genus Fusobacterium.

[0032] [5] According to the treatment agent described in [2], the pathogen causing aspiration pneumonia is selected from one or more of the following bacteria: bacteria belonging to the genus Prevotella, bacteria belonging to the genus Peptostreptococcus, bacteria belonging to the genus Parvimonas, bacteria belonging to the genus Peptoniphilus, bacteria belonging to the genus Finegoldia, and bacteria belonging to the genus Fusobacterium.

[0033] [6] According to the therapeutic agent described in [3], the pathogen causing the lung suppuration or lung abscess is selected from one or more of the following bacteria: bacteria belonging to the genus Prevotella, bacteria belonging to the genus Peptostreptococcus, bacteria belonging to the genus Parvimonas, bacteria belonging to the genus Peptoniphilus, bacteria belonging to the genus Finegoldia, and bacteria belonging to the genus Fusobacterium.

[0034] [7] According to the therapeutic agent described in [1], the pathogen causing aspiration pneumonia, pulmonary suppuration or pulmonary abscess is selected from one or more of the following bacteria: 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 Leptotrichia, bacteria belonging to the genus Peptostreptococcus, bacteria belonging to the genus Parvimonas, bacteria belonging to the genus Veillonella, bacteria belonging to the genus Tissierella, Streptococcus anginosus, and bacteria belonging to the genus Actinomyces.

[0035] [8] According to the treatment agent described in [2], the pathogen causing aspiration pneumonia is selected from one or more of the following bacteria: bacteria belonging to the genus Bacteroides, bacteria belonging to the genus Prevotella, bacteria belonging to the genus Parvimonas, bacteria belonging to the genus Veillonella, and bacteria belonging to the genus Actinomyces.

[0036] [9] According to the therapeutic agent described in [3], the pathogen causing the pulmonary suppuration or pulmonary abscess is selected from one or more of the following bacteria: 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 Leptotrichia, bacteria belonging to the genus Peptostreptococcus, bacteria belonging to the genus Parvimonas, bacteria belonging to the genus Veillonella, bacteria belonging to the genus Tissierella, and Streptococcus anginosus.

[0037]

[10] According to the therapeutic agent described in [1], wherein the daily dose of 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof, converted to 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof is 300 mg on the first day of administration and 150 mg on the second day and thereafter.

[0038]

[11] According to the therapeutic agent described in [2], wherein the daily dose of 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof, converted to 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof, is 300 mg on the first day of administration and 150 mg on the second day and thereafter.

[0039]

[12] According to the therapeutic agent described in [3], wherein the daily dose of 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof, converted to 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof is 300 mg on the first day of administration and 150 mg on the second day and thereafter.

[0040] Advantages of the invention

[0041] According to the present invention, a therapeutic agent for aspiration pneumonia, pulmonary suppuration, or pulmonary abscess may be provided, comprising administering to a patient 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof.

[0042] Description of the implementation plan

[0043] The following describes one embodiment of the present invention in detail.

[0044] The therapeutic agents of this embodiment relate to therapeutic agents for respiratory diseases, particularly those for respiratory infections. More specifically, the therapeutic agents of this embodiment relate to therapeutic agents for aspiration pneumonia, pulmonary suppuration, or lung abscess, comprising administering 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof to a patient, including a human.

[0045] Respiratory tract infection refers to infection occurring in any part of the respiratory tract. In addition, the respiratory tract is a general term for the organs related to breathing, and refers to the organs from the nasal vestibule through the nasal cavity, pharynx, larynx, trachea, bronchi and bronchioles to the alveoli.

[0046] In this article, "aspiration pneumonia" is a respiratory condition involving swelling and infection of the lungs and airways, and is believed to be caused by inhaling harmful substances. Patients with aspiration pneumonia may experience symptoms such as coughing and difficulty breathing.

[0047] In this article, patients with aspiration pneumonia are defined as those who meet the following criteria:

[0048] ● A clear, acutely appearing infiltrative shadow is observed on chest X-ray or CT images.

[0049] ● Clear inhalation has been confirmed, recurrent air obstruction has been confirmed, functional impairment has been confirmed in swallowing function assessment tests, or the patient has a medical complication or history of possible swallowing difficulties.

[0050] ●The patient exhibited characteristic symptoms and inflammation of aspiration pneumonia.

[0051] Examples of characteristic symptoms and inflammation of aspiration pneumonia include cough, purulent sputum, moist rales, dyspnea, fever, positive CRP, leukocytosis, and hypoxemia.

[0052] In this article, "pulmonary suppuration" refers to necrotizing lung infection, also known as lung abscess, and is believed to be caused by bacteria from the mouth and throat being aspirated into the lungs. Patients with pulmonary suppuration may experience symptoms such as fatigue, loss of appetite, night sweats, fever, weight loss, and a cough with phlegm.

[0053] In this article, patients with pulmonary abscess are defined as those who meet the following criteria:

[0054] ● A mass-like shadow or a shadow with internal cavities (nodular shadow, mass shadow) observed on chest X-ray or CT images. (This is unrelated to the presence or absence of an air-fluid level (niveau) attributed to pus accumulation.)

[0055] ●The patient exhibited characteristic symptoms and inflammation of pulmonary suppuration / pulmonary abscess.

[0056] Examples of characteristic symptoms and inflammation of lung suppuration or lung abscess include cough, purulent sputum, moist rales, dyspnea, fever, positive CRP, leukocytosis, and hypoxemia.

[0057] Finding safe and effective compounds against anaerobic pathogens is important for the effective treatment of diseases such as aspiration pneumonia, pulmonary suppuration, or lung abscess. The applicant has discovered that, unlike other quinolone compounds, 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and its pharmaceutically acceptable salts are effective against anaerobic pathogens. For example, injectable formulations of quinolone compounds such as levofloxacin, ciprofloxacin, or pazufloxacin are considered unsuitable as treatments for aspiration pneumonia (Non-Patent Literature 2).

[0058] However, the applicant has discovered that 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and its pharmaceutically acceptable salts are effective against anaerobic pathogens and are effective in treating aspiration pneumonia.

[0059] 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-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 prepared, for example, according to the method described in Patent Document 1 or 2.

[0060] Obligate anaerobic bacteria that cause aspiration pneumonia, lung suppuration, or lung abscess include bacteria belonging to the genus *Bacteroides*, *Prevotella*, *Porphyromonas*, *Fusobacterium*, *Leptotrichia*, *Peptostreptococcus*, and *Parvimos*. Bacteria belonging to the genus *N.*, the genus *Veillonella*, the genus *Tissierella*, the genus *Peptoniphilus*, and the genus *Finegoldia*, as well as facultative anaerobes including the group *Streptococcus anginosus* (which is included in the genus *Streptococcus*) and bacteria belonging to the genus *Actinomyces*. 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 exhibits high antibacterial activity against the anaerobes described above and shows high therapeutic efficacy against aspiration pneumonia, pulmonary suppuration, or lung abscess.

[0061] Examples of pathogens causing aspiration pneumonia include bacteria belonging to the genus Prevotella, Peptostreptococcus, Parvimonas, Peptoniphilus, Finegoldia, Fusobacterium, Bacteroides, and Streptococcus.

[0062] Regarding the treatment of aspiration pneumonia, especially when the causative bacteria are bacteria belonging to the following genera, 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid exhibits high therapeutic efficacy: bacteria belonging to the genus Bacteroides, bacteria belonging to the genus Prevotella, bacteria belonging to the genus Parvimonas, bacteria belonging to the genus Veillonella, or bacteria belonging to the genus Actinomyces.

[0063] Examples of pathogens causing lung suppuration or lung abscess include bacteria belonging to the genus Prevotella, Peptostreptococcus, Parvimonas, Peptoniphilus, Finegoldia, Fusobacterium, Bacteroides, and Streptococcus.

[0064] Regarding the treatment of pulmonary suppuration or lung abscess, especially when the causative bacteria are the following, 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid exhibits high therapeutic efficacy: bacteria belonging to the genus *Prevotella*, bacteria belonging to the genus *Porphyromonas*, bacteria belonging to the genus *Fusobacterium*, bacteria belonging to the genus *Leptotrichia*, bacteria belonging to the genus *Peptostreptococcus*, bacteria belonging to the genus *Parvimonas*, bacteria belonging to the genus *Veillonella*, bacteria belonging to the genus *Tissierella*, or *Streptococcus pharyngis*. (anginosus) group.

[0065] Examples of bacteria belonging to the genus *Prevotella* include *Prevotella denticola*, *Prevotella loescheii*, *Prevotella melaninogenica*, *Prevotella intermedia*, *Prevotella nigrescens*, *Prevotella pallens*, *Prevotella buccae*, *Prevotella oris*, *Prevotella buccalis*, *Prevotella oralis*, *Prevotella bivia*, *Prevotella disiens*, *Prevotella pleuritidis*, *Prevotella bergensis*, *Prevotella timonensis*, or *Prevotella nanceiencis*. From the viewpoint of the therapeutic efficacy of 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, it is more preferable to mention cases where the pathogen causing aspiration pneumonia is *P. melaninogenica*, *P. intermedia*, or *P. buccae*, and cases where the pathogen causing lung suppuration or lung abscess is *P. melaninogenica*, *P. intermedia*, or *P. oralis*.

[0066] Examples of bacteria belonging to the genus Peptostreptococcus include P. anaerobius and P. stomatis.

[0067] Examples of bacteria belonging to the genus *Parvimonas* include *P. micra*. From the viewpoint of the therapeutic efficacy of 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, it is more preferable to mention cases where the causative agent of aspiration pneumonia, pulmonary suppuration, or lung abscess is *P. micra*.

[0068] Examples of bacteria belonging to the genus *Peptoniphilus* include *Peptoniphilus asaccharolyticus*, *Peptoniphilus ivorii*, *Peptoniphilus lacrimalis*, and *Peptoniphilus harei*. From the viewpoint of the therapeutic efficacy 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, the case of *Peptoniphilus asaccharolyticus*, which is the causative agent of aspiration pneumonia, pulmonary suppuration, or pulmonary abscess, is more preferably mentioned.

[0069] Examples of bacteria belonging to the genus Finegoldia include Finegoldia magna. From the viewpoint of the therapeutic efficacy of 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, it is more preferable to mention cases in which the pathogen causing aspiration pneumonia, pulmonary suppuration, or pulmonary abscess is Finegoldia magna.

[0070] Examples of bacteria belonging to the genus *Fusobacterium* include *F. necrophorum*, *F. nucleatum*, *F. mortiferum*, and *F. varium*. From the viewpoint of the therapeutic efficacy 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, it is more preferable to mention cases where the causative agent of lung suppuration or lung abscess is *F. nucleatum* or *F. necrophorum*.

[0071] Examples of bacteria belonging to the genus *Bacteroides* include *Bacteroides fragilis*, *Bacteroides thetaiotaomicron*, *Bacteroides vulgatus*, *Bacteroides ovatus*, *Bacteroides uniformis*, *Bacteroides eggerthii*, *Bacteroides nordii*, *Bacteroides salyersae*, and *Bacteroides massiliensis*. From the viewpoint of the therapeutic efficacy of 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, it is more preferable to mention the case where the causative agent of lung suppuration or lung abscess is *Bacteroides fragilis*.

[0072] Examples of bacteria belonging to the genus *Porphyromonas* include *P. gingivali*, *P. endodontalis*, *P. asaccharolytica*, *P. levii*, and *P. uenonis*. From the viewpoint of the therapeutic efficacy of 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, it is more preferable to mention cases where the pathogen causing lung suppuration or lung abscess is *P. gingivalis* or *P. endodontalis*.

[0073] Examples of bacteria belonging to the genus *Leptotrichia* include *L. buccalis*, *L. hofstadii*, *L. hongkongensis*, *L. shahii*, *L. goodfellowii*, *L. trevisanii*, and *L. wadei*. From the viewpoint of the therapeutic efficacy of 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, it is more preferable to mention the case where the pathogen causing lung suppuration or lung abscess is *L. buccalis*.

[0074] Examples of bacteria belonging to the genus Veillonella include V. parvula, V. atypica, and V. monipelliensis.

[0075] Examples of bacteria belonging to the genus *Tissierella* include *T. creatinini*, *T. creatinophila*, and *T. praeacuta*. From the viewpoint of the therapeutic efficacy of 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, it is more preferable to mention cases where the causative agent of lung suppuration or lung abscess is *T. creatinini*.

[0076] Examples of bacteria belonging to the Streptococcus anginosus group include *Streptococcus intermedius* and *Streptococcus constellatus*. From the viewpoint of the therapeutic efficacy of 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, it is more preferable to mention cases where the causative agents of pulmonary suppuration or lung abscess are *Streptococcus intermedius* and *Streptococcus constellatus*.

[0077] Examples of bacteria belonging to the genus *Actinomyces* include *A. europaeus*, *A. geogiae*, *A. gerncseriae*, *A. graevenitzii*, *A. israelii*, *A. meyeri*, *A. naeslundii*, *A. neuii*, *A. odontolyticus*, *A. radicidentis*, *A. radingae*, *A. turicensis*, *A. urogenitalis*, *A. viscocus*, and the genus *Actinomyces* sp. From the viewpoint of the therapeutic efficacy of 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, it is more preferable to mention the case where the pathogen of aspiration pneumonia is *A. odontolyticus*.

[0078] In this article, the concept of pathogenic bacteria also includes bacteria that have acquired drug resistance. Drug resistance refers to the phenomenon in which an organism becomes resistant to a drug, rendering the drug ineffective or less effective. Examples of drug resistance include resistance to penicillin, cephalosporins, carbapenem, aminoglycosides, macrolides, lincomycin, trimethoprim-sulfamethoxazole, tetracycline, metronidazole, glycopeptides, oxazolidinones, daptomycin, and quinolones.

[0079] Examples of pharmaceutically acceptable additives contained in the above-mentioned pharmaceutical compositions together 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 include excipients, lubricants, binders, disintegrants, stabilizers, flavoring agents, and diluents. These additives are not particularly limited, provided they are suitable for the preparation of pharmaceutical formulations, and where appropriate, additives such as those described in the "Encyclopedia of Pharmaceutical Additives" (Japan Pharmaceutical Additives Association, Pharmaceutical Daily (2007)) may be used.

[0080] The therapeutic agent of this embodiment is administered to a subject, such as a human, using conventional pharmaceutically well-known forms and routes of administration. For example, it can be administered orally or parenterally in formulations such as powders, tablets, capsules, fine granules, granules, syrups, injections, ophthalmic solutions, aqueous nasal drops, aqueous ear drops, or inhalation solutions. That is, the therapeutic agent of this embodiment can be prepared by mixing the active ingredient with physiologically acceptable carriers, excipients, binders, and diluents, for example, in the dosage forms exemplified above.

[0081] In the therapeutic agents of this embodiment, for the purposes of reducing side effects, preparing easily administered small formulations, and preventing the emergence of drug-resistant bacteria, the minimum daily dose of 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof preferably includes 10 mg or more, 20 mg or more, 50 mg or more, 100 mg or more, 125 mg or more, and 150 mg or more. Furthermore, the maximum daily dose preferably includes 300 mg or less, 250 mg or less, 200 mg or less, and 175 mg or less. Examples of daily doses of 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof include 10 mg or more and 300 mg or less, more preferably 20 mg or more and 250 mg or less, further preferably 50 mg or more and 200 mg or less, further preferably 100 mg or more and 200 mg or less, further preferably 125 mg or more and 175 mg or less, and particularly preferably 150 mg. In cases where a pharmaceutically acceptable salt of 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid is used, the value converted to the free form is used as the above-mentioned daily dose. The daily dose may be administered once or divided into 2 to 3 doses, but once daily is preferred. Alternatively, if the effect is insufficient, a dose twice the daily dose may be used.

[0082] Furthermore, loading dosing is preferred to rapidly achieve the target blood concentration. Loading dosing refers to a dosing design that achieves the target blood concentration in an early stage by increasing the daily dose or the number of daily doses during the initial phase of dosing. The initial phase of dosing refers to days 1 to 3 of starting dosing, preferably days 1 to 2, and more preferably day 1. Additionally, as an increase in the daily dose, it is preferable to use twice the daily dose.

[0083] In cases of loading dosing, it is preferable to use twice the daily dose on the first day of dosing. More preferably, in free form, the daily dose of 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof is 300 mg on the first day of dosing and 150 mg on the second day and thereafter.

[0084] The preferred dosage of 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride is 300 mg on the first day of administration and 150 mg on the second day and thereafter. Here, the dosage is expressed as a value obtained by converting 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride to its free form.

[0085] Pharmaceutically acceptable salts may be used in the form of pharmaceutically acceptable salts of 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. Examples of pharmaceutically acceptable salts include salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; salts of 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; or salts of metals, such as sodium, potassium, magnesium, calcium, aluminum, cesium, chromium, cobalt, copper, iron, zinc, platinum, and silver. Among these, hydrochloride salts are particularly preferred.

[0086] "Free form" refers to 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, which is neither a salt, co-crystallization, nor hydrate, and has C 21 H 24 A compound with the molecular formula F3N3O4 and a molecular weight of 439.44.

[0087] The therapeutic agent of this embodiment may consist solely of 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof as the active ingredient. Alternatively, the therapeutic agent of this embodiment may be configured as a pharmaceutical composition containing 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof, and other compounds and / or pharmaceutically acceptable additives acting as the active ingredient.

[0088] The pharmaceutical composition may contain one or more compounds as other compounds serving as active ingredients and / or pharmaceutically acceptable additives. For example, the pharmaceutical composition is prepared by mixing 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-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 of other compounds serving as active ingredients and additives.

[0089] As described above, according to this embodiment, a technology relating to a therapeutic agent with high therapeutic efficacy and safety against aspiration pneumonia, pulmonary suppuration, or pulmonary abscess can be provided. By using appropriate compositions as described herein, adequate therapeutic effects can be achieved even at low doses, while reducing side effects and the frequency of drug-resistant bacterial development. (Example)

[0090] The invention will be described in more detail below by way of illustrated embodiments, but the scope of the invention is not limited to these embodiments.

[0091] A 150 mg injection of 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (hereinafter also referred to as Investigational New Drug A) was prepared according to the method disclosed in International Publication No. WO 2016 / 195014.

[0092] The "150 mg" in the 150 mg injection indicates the weight of 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride converted to its free form. In preparing the injection, 162.5 mg (converted to free form: 150 mg) of 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride was used. (Experimental Example 1) Aspiration pneumonia

[0093] Thirteen subjects suspected of having aspiration pneumonia who met the following criteria were given an intravenous dose of the investigational new drug A for 7–14 days.

[0094] ● Individuals aged 16 years or older with acute, well-defined infiltrative shadows observed on chest X-ray or CT images taken within 48 hours prior to the start of administration.

[0095] ●Identify clear signs of inhalation, airway obstruction, or difficulty swallowing, and have a history or condition that suggests the possibility of difficulty swallowing.

[0096] ●The patient exhibited characteristic symptoms and inflammation of aspiration pneumonia.

[0097] On the first day of administration, administer two doses of Investigational New Drug A (300 mg / day), and on the second day, administer one dose of Investigational New Drug A (150 mg / day), then maintain the same dose (150 mg / day). Each dose is administered intravenously over approximately 1 hour.

[0098] (Experimental Example 2) Lung suppuration or lung abscess

[0099] Eleven subjects suspected of having pulmonary suppuration or pulmonary abscess who met the following criteria were given the investigational new drug A7 to 14 days intravenously.

[0100] ● Individuals aged 16 years or older with a mass-like or cavitary shadow (nodular shadow, mass shadow) observed on a chest X-ray or CT scan taken within 48 hours prior to the start of administration. This is unrelated to the presence or absence of an air-fluid level (niveau) attributable to pus accumulation.

[0101] ●The patient presents with characteristic symptoms and inflammation of lung suppuration or lung abscess.

[0102] On the first day of administration, administer two doses of Investigational New Drug A (300 mg / day), and on the second day, administer one dose of Investigational New Drug A (150 mg / day), then maintain the same dose (150 mg / day). Each dose is administered intravenously over approximately 1 hour.

[0103] Based on the criteria for clinical efficacy against pneumonia described in the "New Regulations for the Clinical Evaluation of Antibacterial Drugs for Respiratory Infections (Second Edition)" (Nikkei Journal of the Japan Chemical Society 2012; 60(1): 30-45.9), the following criteria were established to determine the clinical efficacy of Case 1 and Case 2. The primary evaluation item was the efficacy rate of the investigational new drug A at the end or discontinuation of administration.

[0104] In this article, "end of dosing" refers to the evaluation date the day following the completion date of dosing of the investigational new drug A. "Discontinuation" refers to the evaluation date implemented within 3 days from the last dosing date of the investigational new drug A or the date of discontinuation. Furthermore, "end of dosing or discontinuation" is expressed as "end of treatment (EOT)". Additionally, CRP is short for C-reactive protein and is one of the acute-phase reactants produced in a short period of time in response to various inflammations. It is a useful indicator for observing treatment efficacy because it rises within hours in bacterial infections such as pneumonia and rapidly decreases as inflammation subsides.

[0105] ● Early drug efficacy assessment and at the end of treatment (EOT)

[0106] Three days after administration, the early drug efficacy assessment was determined according to Table 1 in three levels: "Early therapeutic effect", "No early therapeutic effect" and "Cannot be determined".

[0107] "Early therapeutic effect" is defined as cases in which significant improvement is observed 3 days after administration (regardless of whether administration is completed or continued after 4 days). Additionally, in cases where CRP levels and chest X-rays do not improve 3 days after administration compared to before administration, "early therapeutic effect" is defined as cases in which clinical symptoms and body temperature have improved, even if there is no change or worsening of CRP or chest X-ray findings.

[0108] If CRP or chest X-ray findings remain unchanged or worsen, and clinical symptoms and body temperature do not change or improve, the study is deemed "no early treatment response." Taking full account of the participants' safety, investigators and other relevant personnel make appropriate decisions, such as discontinuing the clinical trial and switching to other antibiotics. Samples for microbiological evaluation should be collected before initiating appropriate alternative antibiotic therapy.

[0109] Furthermore, if the discontinuation date is the start date of administration (day 0) or the second day of administration (day 1), it is considered unnecessary to determine the efficacy of the drug in the early stages. In cases where administration begins on the third day (day 2) or later, the test results at the time of discontinuation should be used for determination.

[0110] For the end of treatment (EOT), clinical efficacy at the end of administration or discontinuation is determined according to Table 1 in three levels: "Effective", "Ineffective", and "Indeterminate". In cases where treatment is discontinued after the day following the end of administration, clinical efficacy at the end of administration is determined, but clinical efficacy at discontinuation is not required.

[0111] Furthermore, treatment is deemed "ineffective" in cases of discontinuation of treatment or when an investigational new drug is switched to an alternative antibiotic after its administration is completed. However, this does not apply to cases where treatment was deemed "effective" according to the criteria in Table 1 at the end of treatment (EOT), even if the treatment is switched to an alternative antibiotic. In cases of switching to an alternative antibiotic, in principle, prescribed tests, examinations, and end-of-treatment assessments should be conducted prior to the switch.

[0112] [Table 1]

[0113] Table 1. Early drug efficacy assessment and treatment end criteria

[0114]

[0115] Tables 2 and 3 show the results of early drug efficacy assessments and the end of treatment in Case 1 and Case 2.

[0116] [Table 2]

[0117] Table 2. Early Drug Efficacy Assessment

[0118]

[0119] [Table 3]

[0120] Table 3. At the end of treatment

[0121]

[0122] The efficiency is a value obtained by the following formula.

[0123] Effectiveness = (Number of objects rated as "effective" ÷ Number of objects rated as "effective" or "ineffective") × 100 (%)

[0124] Tables 2 and 3 show that 7-[(3S,4S)-3-{(cyclopropylamino)methyl}-4-fluoropyrrolidone-1-yl]-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof has a high therapeutic effect on aspiration pneumonia, pulmonary suppuration, or lung abscess. In particular, the efficacy rate at the end of treatment was significantly high, reaching 100% for aspiration pneumonia and 91% for pulmonary suppuration or lung abscess.

[0125] Tables 4 and 5 show the microbiological efficacy of the pathogens in Test Case 1 and Test Case 2.

[0126] [Table 4]

[0127] Table 4. Based on the microbiological efficacy of pathogens (aspiration pneumonia)

[0128]

[0129] [Table 5]

[0130] Table 5. Based on the microbiological function of pathogenic bacteria (lung suppuration / lung abscess)

[0131]

[0132] Tables 4 and 5 show that 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 has a high antibacterial effect against pathogens causing aspiration pneumonia, pulmonary suppuration, or lung abscess.

[0133] Industrial applicability

[0134] According to this implementation plan, it is possible to provide a treatment for aspiration pneumonia, lung suppuration, or lung abscess, which is industrially useful.

Claims

1. A treatment agent for aspiration pneumonia, pulmonary suppuration or pulmonary abscess, comprising 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 as the active ingredient.

2. A treatment agent for aspiration pneumonia, comprising 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 as the active ingredient.

3. A therapeutic agent for lung suppuration or lung abscess, comprising 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 as the active ingredient.

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