阅读说明：本技术 吸入性肺炎、肺化脓或肺脓肿的治疗剂 (Therapeutic agent for aspiration pneumonia, lung suppuration or lung abscess ) 是由 小田岛正明 谷冈幸代子 须之内孝明 田渊亚沙子 于 2018-06-15 设计创作，主要内容包括：本发明涉及更安全且更有效的呼吸道感染的治疗剂。吸入性肺炎、肺化脓或肺脓肿的治疗剂,该药剂含有7-[(3S,4S)-3-{(环丙基氨基)甲基}-4-氟吡咯烷-1-基]-6-氟-1-(2-氟乙基)-8-甲氧基-4-氧代-1,4-二氢喹啉-3-羧酸或其药学上可接受的盐作为活性成分。(The present invention relates to a safer and more effective therapeutic agent for respiratory tract infection. A therapeutic agent for aspiration pneumonia, lung suppuration or lung abscess, which comprises 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 as an active ingredient.)

1. A therapeutic agent for aspiration pneumonia, lung suppuration or lung abscess, which comprises 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 as an active ingredient.

2. A therapeutic agent for aspiration pneumonia, which comprises 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 as an active ingredient.

3. A therapeutic agent for lung suppuration or lung abscess, which comprises 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 as an active ingredient.

4. The therapeutic agent according to claim 1, wherein the pathogenic bacteria of aspiration pneumonia, lung suppuration or lung abscess is one or more bacteria selected from the group consisting of: a bacterium belonging to the genus Prevotella, a bacterium belonging to the genus Peptostreptococcus, a bacterium belonging to the genus Micromonospora, a bacterium belonging to the genus Peptophilus, a bacterium belonging to the genus Fengolder and a bacterium belonging to the genus Clostridium.

5. A therapeutic agent according to claim 2, wherein the pathogenic bacteria of aspiration pneumonia are one or more bacteria selected from the group consisting of: a bacterium belonging to the genus Prevotella, a bacterium belonging to the genus Peptostreptococcus, a bacterium belonging to the genus Micromonospora, a bacterium belonging to the genus Peptophilus, a bacterium belonging to the genus Fengolder and a bacterium belonging to the genus Clostridium.

6. The therapeutic agent according to claim 3, wherein the pathogenic bacteria of lung suppuration or lung abscess are one or more bacteria selected from the group consisting of: a bacterium belonging to the genus Prevotella, a bacterium belonging to the genus Peptostreptococcus, a bacterium belonging to the genus Micromonospora, a bacterium belonging to the genus Peptophilus, a bacterium belonging to the genus Fengolder and a bacterium belonging to the genus Clostridium.

7. The therapeutic agent according to claim 1, wherein the pathogenic bacteria of aspiration pneumonia, lung suppuration or lung abscess is one or more bacteria selected from the group consisting of: bacteria belonging to the genus Bacteroides, bacteria belonging to the genus Prevotella, bacteria belonging to the genus Porphyromonas, bacteria belonging to the genus Clostridium, bacteria belonging to the genus cilium, bacteria belonging to the genus Peptostreptococcus, bacteria belonging to the genus Micromonospora, bacteria belonging to the genus Veillonella, bacteria belonging to the genus Tylschaeta, Streptococcus angina, and bacteria belonging to the genus Actinomyces.

8. A therapeutic agent according to claim 2, wherein the pathogenic bacteria of aspiration pneumonia are one or more bacteria selected from the group consisting of: bacteria belonging to the genus Bacteroides, bacteria belonging to the genus Prevotella, bacteria belonging to the genus Micromonospora, bacteria belonging to the genus Veillonella, and bacteria belonging to the genus Actinomyces.

9. The therapeutic agent according to claim 3, wherein the pathogenic bacteria of lung suppuration or lung abscess are one or more bacteria selected from the group consisting of: bacteria belonging to the genus Bacteroides, bacteria belonging to the genus Prevotella, bacteria belonging to the genus Porphyromonas, bacteria belonging to the genus Clostridium, bacteria belonging to the genus cilium, bacteria belonging to the genus Peptostreptococcus, bacteria belonging to the genus Micromonospora, bacteria belonging to the genus Veillonella, bacteria belonging to the genus Thai, and Streptococcus angina.

10. The therapeutic agent according to claim 1, wherein the daily dose of 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, converted into 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, is 300mg on the day on which administration is started, and 150mg the following day and thereafter of administration.

11. The therapeutic agent according to claim 2, wherein the daily dose of 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, converted to 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 is 300mg on the day of initiation of administration, and 150mg the following day and thereafter of administration.

12. The therapeutic agent according to claim 3, wherein the daily dose of 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, converted to 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 is 300mg on the day of initiation of administration, and 150mg the following day and thereafter of administration.

Technical Field

The present invention relates to a therapeutic agent for aspiration pneumonia, lung suppuration or lung abscess.

Background

Since the development of norfloxacin, quinolone carboxylic acid antibacterial agents called new quinolones have been developed worldwide, and many new quinolone antibacterial agents are now widely used as therapeutic agents for infectious diseases.

Meanwhile, a quinolone carboxylic acid derivative represented by general formula (1) has been disclosed by the applicant (patent document 1).

[ formula 1]

In the formula (1), R¹Represents an alkyl group having 1 to 6 carbon atoms optionally substituted with one or more halogen atoms; cycloalkyl having 3 to 6 carbon atoms optionally substituted with one or more halogen atoms; or aryl or heteroaryl, optionally substituted by one or more identical or different substituents selected from halogen atoms and amino groups; r²Represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a pharmaceutically acceptable cation; r³Represents a hydrogen atom, a halogen atom, a hydroxyl group, an amino group or an alkyl group having 1 to 3 carbon atoms; r⁴Represents a hydrogen atom or a halogen atom; r⁵Represents a fluorine atom; r⁶Represents a hydrogen atom or a fluorine atom; and A represents a nitrogen atom or ═ C-X (wherein 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).

In addition, patent document 1 discloses 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 as one of the quinolone carboxylic acid derivatives described above. In addition, hydrochloride salts thereof are disclosed in patent document 2.

In addition, one example of a respiratory infection includes aspiration pneumonia. Aspiration pneumonia is a disease that accounts for most of pneumonia in the elderly, and is a serious disease that is refractory, recurrent, and has a high mortality rate (non-patent document 1). Pathogenic bacteria of aspiration pneumonia include anaerobic bacteria, Staphylococcus aureus (Staphylococcus aureus), and enteric bacteria (non-patent document 1), but a method for effectively treating aspiration pneumonia has not been established so far. Currently marketed quinolone formulations include levofloxacin, ciprofloxacin, pazufloxacin, moxifloxacin, sitafloxacin and ganofloxacin. Most of the initial treatments for aspiration pneumonia, which is a highly serious disease, use injectable formulations, but among the above quinolone formulations, levofloxacin, ciprofloxacin, and pazufloxacin, which can be utilized to obtain their injectable formulations, have insufficient antibacterial activity against anaerobic bacteria, and are not recommended for use in patients suspected of having aspiration pneumonia (non-patent document 2). Of oral preparations, sitafloxacin, moxifloxacin and gatifloxacin may be effective against anaerobic bacterial infection (non-patent documents 3 to 5), but there has been no report on a paper with strong evidence for aspiration pneumonia, and an effective therapeutic method has not been established so far.

As in the case of aspiration pneumonia, examples of respiratory tract infections mainly caused by anaerobic bacteria include lung abscesses (non-patent document 6). Although there are reports of therapeutic efficacy observed for moxifloxacin and pazufloxacin (non-patent documents 3 to 4 and non-patent document 7), they have not been established as an effective therapeutic method so far.

Reference list

Non-patent document

Non-patent document 1: international Association of Japan, 35 468, No. 99, 11/2010, page 2746-2751.

Non-patent document 2: a general community related person japanese respirator society, "medical science" mediate Seki "discloses a lung inflammation" ガイドライン "page 23.

Non-patent document 3: infection (Munich, Germany) (2008), 36, (1), 23-30.

Non-patent document 4: expert Review of Respiratory Medicine (2007), 1(1), 111-.

Non-patent document 5: commonly-used people, japan respirator society, "adult pneumonia", ガイドライン 2017 ン, page 24.

Non-patent document 6: institute of respiratory japan, ibid.35468, 49 (9): 623-628, 2011.

Non-patent document 7: nippon Kagaku Ryoho Gakkai Zasshi (1999),47 (supplement 1),196- "203".

Patent document

Patent document 1: international publication WO 2005/026147 pamphlet

Patent document 2: international publication No. WO 2013/069297

Summary of The Invention

Technical problem

The object of the present invention is to provide a novel therapeutic agent for respiratory tract infection.

Means for solving the problems

The present inventors have studied highly effective and safe therapeutic agents for respiratory tract infections. The present inventors have conducted extensive studies on the above-mentioned problems and found that 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 is extremely effective as a therapeutic agent for aspiration pneumonia, lung suppuration or lung abscess, and completed the present invention.

The gist of the present invention is as follows:

[1] a therapeutic agent for aspiration pneumonia, lung suppuration or lung abscess, which comprises 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 as an active ingredient.

[2] A therapeutic agent for aspiration pneumonia, which comprises 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 as an active ingredient.

[3] A therapeutic agent for lung suppuration or lung abscess, which comprises 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 as an active ingredient.

[4] The therapeutic agent according to [1], wherein the pathogenic bacterium of aspiration pneumonia, lung suppuration or lung abscess is one or more bacteria selected from the group consisting of: bacteria belonging to the genus Prevotella (Prevotella), bacteria belonging to the genus Streptococcus (Peptostreptococcus), bacteria belonging to the genus Micromonospora (Parvimonas), bacteria belonging to the genus Peptophilus (Peptophilus), bacteria belonging to the genus Fengoldia (Finegoldia), and bacteria belonging to the genus Clostridium (Fusobacterium).

[5] The therapeutic agent according to [2], wherein the pathogenic bacteria of aspiration pneumonia are one or more bacteria selected from the group consisting of: bacteria belonging to the genus Prevotella (Prevotella), bacteria belonging to the genus Streptococcus (Peptostreptococcus), bacteria belonging to the genus Micromonospora (Parvimonas), bacteria belonging to the genus Peptophilus (Peptophilus), bacteria belonging to the genus Fengoldia (Finegoldia), and bacteria belonging to the genus Clostridium (Fusobacterium).

[6] The therapeutic agent according to [3], wherein the pathogenic bacteria of lung suppuration or lung abscess is one or more bacteria selected from the group consisting of: bacteria belonging to the genus Prevotella (Prevotella), bacteria belonging to the genus Streptococcus (Peptostreptococcus), bacteria belonging to the genus Micromonospora (Parvimonas), bacteria belonging to the genus Peptophilus (Peptophilus), bacteria belonging to the genus Fengoldia (Finegoldia), and bacteria belonging to the genus Clostridium (Fusobacterium).

[7] The therapeutic agent according to [1], wherein the pathogenic bacterium of aspiration pneumonia, lung suppuration or lung abscess is one or more bacteria selected from the group consisting of: bacteria belonging to the genus Bacteroides (Bacteroides), bacteria belonging to the genus Prevotella (Prevotella), bacteria belonging to the genus Porphyromonas (Porphyromonas), bacteria belonging to the genus Clostridium (Fusobacterium), bacteria belonging to the genus Leptotrichia (Leptotrichia), bacteria belonging to the genus Streptococcus digestus (Peptostreptococcus), bacteria belonging to the genus Micromonoses (Parvimonas), bacteria belonging to the genus Veillonella (Veilonella), bacteria belonging to the genus Tissella (Tissierella), the group Streptococcus angina (Streptococcus angularis), and bacteria belonging to the genus Actinomyces (Actinomyces).

[8] The therapeutic agent according to [2], wherein the pathogenic bacteria of aspiration pneumonia are one or more bacteria selected from the group consisting of: bacteria belonging to the genus Bacteroides (Bacteroides), bacteria belonging to the genus Prevotella (Prevotella), bacteria belonging to the genus Micromonospora (Parvimonas), bacteria belonging to the genus Veillonella (Veillonella), and bacteria belonging to the genus Actinomycetes (Actinomyces).

[9] The therapeutic agent according to [3], wherein the pathogenic bacteria of lung suppuration or lung abscess is one or more bacteria selected from the group consisting of: bacteria belonging to the genus Bacteroides (Bacteroides), bacteria belonging to the genus Prevotella (Prevotella), bacteria belonging to the genus Porphyromonas (Porphyromonas), bacteria belonging to the genus Clostridium (Fusobacterium), bacteria belonging to the genus Leptotrichia (Leptotrichia), bacteria belonging to the genus Streptococcus digestus (Peptostreptococcus), bacteria belonging to the genus Micromonoses (Parvimonas), bacteria belonging to the genus Veillonella (Veilonella), bacteria belonging to the genus Tictella (Tissella), and the group Streptococcus angina (Streptococcus angularis).

[10] The therapeutic agent according to [1], wherein the daily dose of 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, converted to 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 is 300mg on the day of initiation of administration, and 150mg the following day and thereafter of administration.

[11] The therapeutic agent according to [2], wherein the daily dose of 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, converted to 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 is 300mg on the day of initiation of administration, and 150mg the following day and thereafter of administration.

[12] The therapeutic agent according to [3], wherein the daily dose of 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, converted to 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 is 300mg on the day of initiation of administration, and 150mg the following day and thereafter of administration.

Advantageous effects of the invention

According to the present invention, there can be provided a therapeutic agent for aspiration pneumonia, lung suppuration or lung abscess, which comprises administering 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 to a patient.

Description of the embodiments

One embodiment of the present invention is described in detail below.

The therapeutic agent of the present embodiment relates to a therapeutic agent for respiratory diseases, particularly to a therapeutic agent for respiratory infections. More specifically, the therapeutic agent of the present embodiment relates to a therapeutic agent for inhalation pneumonia, lung suppuration or lung abscess, which comprises administering 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 to a patient, including a human.

Respiratory infections refer to infections occurring anywhere in the respiratory tract. Further, the respiratory tract is a generic term of 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.

Herein, "aspiration pneumonia" is a respiratory tract disorder including swelling and infection of the lungs and airways, and is considered to be caused by inhalation of harmful substances. Patients with aspiration pneumonia may have symptoms such as coughing and dyspnea.

Herein, a patient suffering from aspiration pneumonia means a person who meets the following criteria:

acute appearing sharp infiltrative shadows are observed on chest X-ray or CT images.

A clear inhalation has been confirmed, a recurrent gas infarct has been confirmed, a dysfunction has been confirmed in a swallowing function assessment test, or a disease complication or history that the patient has a likelihood of having difficulty swallowing.

The patients exhibited symptoms and inflammation characteristic of aspiration pneumonia.

Cough, purulent sputum, rales, dyspnea, fever, CRP positive, leukocytosis, hypoxemia, and the like are exemplified as characteristic symptoms and inflammation of aspiration pneumonia.

Herein, "lung suppuration" is a necrotic lung infection, which is also called lung abscess, and is thought to be caused by the inhalation of bacteria in the mouth and throat into the lungs. Patients with lung suppuration may have symptoms such as fatigue, loss of appetite, sleeping sweat, fever, weight loss, and phlegm cough.

Herein, a patient suffering from lung suppuration means a person who meets the following criteria:

a lump shadow or a shadow with a hollow inside (a nodule shadow or a lump shadow) is observed on the chest X-ray or CT image. (independent of the presence or absence of a plane of gas-liquid (niveau) due to accumulation of pus.)

Patients exhibit symptoms and inflammation characteristic of lung suppuration/lung abscess.

Cough, purulent sputum, rales, dyspnea, fever, CRP positive, leukocytosis, hypoxemia, and the like are exemplified as characteristic symptoms and inflammation of lung suppuration or lung abscess.

Finding safe and effective compounds against anaerobic pathogens is important for the effective treatment of diseases such as aspiration pneumonia, lung suppuration or lung abscess. Applicants have discovered that, unlike other quinolone compounds, 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 its pharmaceutically acceptable salts are effective against anaerobic pathogenic bacteria. For example, an injection of a quinolone compound such as levofloxacin, ciprofloxacin, or pazufloxacin is considered to be unsuitable as a therapeutic agent for aspiration pneumonia (non-patent document 2).

However, applicants have found that 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 its pharmaceutically acceptable salts are effective against anaerobic pathogenic bacteria and are effective in the treatment of aspiration pneumonia.

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 prepared, for example, according to the method described in patent document 1 or 2.

The obligate anaerobic bacteria as pathogenic bacteria of aspiration pneumonia, lung suppuration or lung abscess include bacteria belonging to the genus Bacteroides (Bacteroides), bacteria belonging to the genus preraoh (Prevotella), bacteria belonging to the genus Porphyromonas (Porphyromonas), bacteria belonging to the genus clostridium (Fusobacterium), bacteria belonging to the genus leptospirillum (Leptotrichia), bacteria belonging to the genus Peptostreptococcus (Peptostreptococcus), bacteria belonging to the genus Parvimonas (Parvimonas), bacteria belonging to the genus Veillonella (Veillonella), bacteria belonging to the genus tympana (tisella), bacteria belonging to the genus peptostreptophilus (peptostreptophyces) and bacteria belonging to the genus gorella (Finegoldia), and the anaerobic bacteria include Streptococcus pharyngis (Streptococcus coccus) which belongs to the genus Actinomyces and Actinomyces (Actinomyces). 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 a high antibacterial activity against the anaerobic bacteria described above and exhibits a high therapeutic effect against aspiration pneumonia, lung suppuration or lung abscess.

Examples of pathogenic bacteria of inhalation pneumonia include bacteria belonging to the genus Prevotella (Prevotella), bacteria belonging to the genus Peptostreptococcus (Peptostreptococcus), bacteria belonging to the genus Micromonospora (Parvimonas), bacteria belonging to the genus Peptophilus (Peptophilus), bacteria belonging to the genus Fengoldia (Finegoldia), bacteria belonging to the genus Fusobacterium (Fusobacterium), bacteria belonging to the genus Bacteroides (Bacteroides), and bacteria belonging to the genus Streptococcus (Streptococcus).

With respect to the treatment of aspiration pneumonia, especially when the pathogenic bacteria of aspiration pneumonia are the following, 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 a high therapeutic effect: a bacterium belonging to the genus Bacteroides (Bacteroides), a bacterium belonging to the genus Prevotella (Prevotella), a bacterium belonging to the genus Micromonospora (Parvimonas), a bacterium belonging to the genus Veillonella (Veillonella), or a bacterium belonging to the genus Actinomyces (Actinomyces).

Examples of pathogenic bacteria of lung suppuration or lung abscess include bacteria belonging to the genus Prevotella, bacteria belonging to the genus Peptostreptococcus, bacteria belonging to the genus Micromonospora, bacteria belonging to the genus Peptophilus, bacteria belonging to the genus Fengoldia (Finegoldia), bacteria belonging to the genus Fusobacterium, bacteria belonging to the genus Bacteroides (Bacteroides), and bacteria belonging to the genus Streptococcus.

With respect to the treatment of lung suppuration or lung abscess, especially when the pathogenic bacteria of lung suppuration or lung abscess are the following, 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 a high therapeutic effect: bacteria belonging to the genus Prevotella (Prevotella), bacteria belonging to the genus Porphyromonas (Porphyromonas), bacteria belonging to the genus Clostridium (Fusobacterium), bacteria belonging to the genus Leptotrichia (Leptotrichia), bacteria belonging to the genus Streptococcus (Peptostreptococcus), bacteria belonging to the genus Micromonospora (Parvimonas), bacteria belonging to the genus Veillonella (Veillonella), bacteria belonging to the genus Thailand (Tissella), or the group Streptococcus angina (Streptococcus anginosus).

Examples of bacteria belonging to the genus Prevotella (Prevotella) include Prevotella denticola (p.denticola), Prevotella lorella rockii (p.loescheii), Prevotella melanogenes (p.melaninogenica), Prevotella intermedia (p.internmedia), Prevotella nigrescens (p.nigrescens), Prevotella pallidum (p.pallens), Prevotella buccae (p.buccae), Prevotella oralis (p.oris), Prevotella oralis (p.buccalis), Prevotella oralis (p.oris), Prevotella oralis (p.buccalcois), Prevotella oralis (p.oralis), Prevotella bivialis (p.bivia), Prevotella saccharicola (p.disiensis), Prevotella pleuritis (p.mitilis), Prevotella radiculiginis (p.argentis), and Prevotella. From the viewpoint of therapeutic efficacy of 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, more preferably, cases are mentioned in which the pathogenic bacterium of inhalation pneumonia is melanosporum (p.melaninogenica), preprolithia intermedia (p.intermedia) or buchnera (p.buccae), and cases in which the pathogenic bacterium of lung suppuration or lung abscess is melanosporum (p.melaninogenica), preprolithia intermedia (p.intermedia) or oral prevolithia (p.oralis).

Examples of bacteria belonging to the genus streptococcus (Peptostreptococcus) include anaerobically digested streptococcus (p.anaerobicus) and stomatitis digested streptococcus (p.stomatis).

Examples of bacteria belonging to the genus of micromonospora (Parvimonas) include micromonospora (p. From the viewpoint of the therapeutic efficacy of 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, more preferably, mention is made of the case where the pathogenic bacterium of aspiration pneumonia, lung suppuration or lung abscess is micromonospora parvum (p.

Examples of the bacterium belonging to the genus of the peptone (Peptoniphilus) include saccharophilus saccharolyticus (Peptoniphilus acarochanolicus), peptone (Peptoniphilus ivorii), lacrimal gland peptone (Peptoniphilus lacrimalis), and peptone (Peptoniphilus harei). From the viewpoint of the therapeutic efficacy of 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, more preferably, mention is made of the case where the pathogenic bacterium of aspiration pneumonia, lung suppuration or lung abscess is saccharophilus undetaceae (peptostreptoniphilus).

Examples of the bacterium belonging to the genus Fengolder (Finegoldia) include large Fengolder (Finegoldiamagna). From the viewpoint of the therapeutic efficacy of 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, more preferably mentioned is the case where the pathogenic bacterium of aspiration pneumonia, lung suppuration or lung abscess is large fengolder bacteria (Finegoldia magna).

Examples of the bacterium belonging to the genus clostridium (Fusobacterium) include Fusobacterium necrophorum (f.necrophorum), Fusobacterium nucleatum (f.nuclearum), Fusobacterium mortiferum (f.mortiferum), and Fusobacterium proteorum (f.variaum). From the viewpoint of the therapeutic efficacy of 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, more preferably, mention is made of the case where the pathogenic bacterium of lung suppuration or lung abscess is fusobacterium nucleatum (f.tuberculosis) or fusobacterium necrophorum (f.necrophorum).

Examples of bacteria belonging to the genus Bacteroides (Bacteroides) include Bacteroides fragilis (b.fragilis), Bacteroides thetaiotaomicron (b.thetaiotaomicron), Bacteroides vulgatus (b.vulgatus), Bacteroides ovatus (b.ovatus), Bacteroides monoformis (b.uniformis), Bacteroides ehrlichiae (b.eggerthii), b.nordii, b.salysesae and Bacteroides massiliensis (b.massellasias). From the viewpoint of the therapeutic efficacy of 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, more preferably, mention is made of the case where the pathogenic bacterium of lung suppuration or lung abscess is bacteroides fragilis (b.fragilis).

Examples of bacteria belonging to the genus Porphyromonas (Porphyromonas) include Porphyromonas gingivalis (p.gingivali), Porphyromonas endodontium (p.endontonottalis), Porphyromonas saccharolytica (p.asaccharolytica), Porphyromonas lii (p.levii), and p.uenonis. From the viewpoint of the therapeutic efficacy of 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, more preferably, mention is made of the case where the pathogenic bacterium of lung suppuration or lung abscess is porphyromonas gingivalis (p.gingivalis) or porphyromonas dental pulp (p.endodontalis).

Examples of bacteria belonging to the genus fibrotrichia (leptichia) include oral fibrotrichia (l.buccalis), cilium hirsutum (l.hofstadii), fibrillinus hongkongensis (l.hongkongensis), fibrillinus shawinii (l.shahii), fibrillinus guldiferulea (l.goodfellowii), fibrillinus terniformis (l.trevisanii), and fibrillinus wednesis (l.wadei). From the viewpoint of the therapeutic efficacy of 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, more preferably mentioned is the case where the pathogenic bacterium of lung suppuration or lung abscess is trichoderma orale (l.

Examples of bacteria belonging to the genus Veillonella (Veillonella) include Veillonella parvula (v.parvula), atypical Veillonella (v.atypica), and v.montpelliensis.

Examples of bacteria belonging to the genus tympanella (Tissierella) include tympanella creatinine (t.creatinini), tympanophilus creatinine (t.creatinophila), and tympana extremophila (t.praeacuta). From the viewpoint of the therapeutic efficacy of 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, more preferably mentioned is the case where the pathogenic bacterium of lung suppuration or lung abscess is t.creatinii.

Examples of bacteria belonging to the group of Streptococcus angiitis (Streptococcus anginosus) include Streptococcus intermedius (s.intermedia) and Streptococcus constellatus (s.constellatus). From the viewpoint of the therapeutic efficacy of 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, more preferably, cases are mentioned in which the pathogenic bacteria of lung suppuration or lung abscess are streptococcus intermedius (s.intermedius) and streptococcus constellatus (s.constellatus).

Examples of bacteria belonging to the genus actinomycetes (actinomycetes) include european actinomycetes (a.europaeus), georgiae actinomycetes (a.geoorgiae), goethi actinomycetes (a.gerencsieae), grafeniz actinomycetes (a.gravenitzii), chlamydia actinomycetes (a.israelii), meissypium meyeri, naeslundii (a.naeslundii), neuturi actinomycetes (a.neuui), cariogenic actinomycetes (a.odontolyticus), odontobiomycetes (a.radiatidoides), rythromyces ruitinus (a.radadaae), actinomycetes (a.turingiensis), urogenital actinomycetes (a.urogenisis), mucositis (a.viscosus) and actinomycetes (actinomycetes sp). From the viewpoint of therapeutic efficacy of 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, more preferably, mention is made of the case where the pathogenic bacterium of aspiration pneumonia is actinomyces carious (a. odontolyticus).

Herein, pathogenic bacteria are a concept that also includes bacteria that have acquired resistance to drugs. Drug resistance refers to a phenomenon in which an organism has resistance to a drug and the drug is ineffective or becomes less effective. Examples of resistance include resistance to penicillin, resistance to cephalosporins, resistance to carbapenem, resistance to aminoglycosides, resistance to macrolides, resistance to lincomycin, resistance to trimethoprim-sulfamethoxazole, resistance to tetracycline, resistance to metronidazole, resistance to glycopeptides, resistance to oxazolidinones, resistance to daptomycin, and resistance to quinolones.

Examples of pharmaceutically acceptable additives contained in the above-mentioned pharmaceutical composition together with 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 include excipients, lubricants, binders, disintegrants, stabilizers, flavors and diluents. These additives are not particularly limited as long as they can be used for preparing pharmaceutical preparations, and, for example, those described in "medicine supplement dictionary (typography, day of medicine (2007))", in japan can be used as appropriate.

The therapeutic agents of the present embodiment are administered to a subject, such as a human, by employing conventional pharmaceutically well-known forms and routes of administration. For example, preparations such as powder, tablet, capsule, fine granule, syrup, injection, ophthalmic solution, aqueous nasal drops, aqueous ear drops or inhalation solution can be administered orally or parenterally. That is, the therapeutic agent of the present embodiment can be prepared by mixing the active ingredient with physiologically acceptable carriers, excipients, binders, diluents, and the like, for example, in the dosage forms as exemplified above.

In the therapeutic agent of the present embodiment, the minimum daily dose of 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 preferably includes 10mg or more, 20mg or more, 50mg or more, 100mg or more, 125mg or more, and 150mg or more in terms of reducing side effects, preparing a small-sized preparation which is easy to take, and preventing the occurrence of drug-resistant bacteria. Further, the maximum daily dose preferably includes 300mg or less, 250mg or less, 200mg or less, and 175mg or less. Examples of the daily dose of 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 include 10mg or more and 300mg or less, more preferably 20mg or more and 250mg or less, further preferably 50mg or more and 200mg or less, further preferably 100mg or more and 200mg or less, further preferably 125mg or more and 175mg or less, and particularly preferably 150 mg. In the case of using a pharmaceutically acceptable salt of 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 value converted into the free form is used as the above-mentioned daily dose. The dose for one day may be administered once or may be divided into 2 to 3 times (administration), but is preferably administered once per day. In addition, if the effect is insufficient, a dose of twice the daily dose may be used.

In addition, loading administration is preferably performed so as to quickly reach the target blood concentration. The loading dose means a dose design that reaches a target blood concentration at an early stage by increasing a daily dose or the number of daily doses at an initial stage of the dose. The initial period of administration means 1 st to 3 rd days from the start of administration, preferably means 1 st to 2 nd days from the start of administration, and further preferably 1 st day from the start of administration. In addition, as an increase in the daily dose, it is preferable to use twice the daily dose.

In the case of administration of a loading dose, it is preferable to use twice the daily dose on the first day of the start of administration. A more preferable daily dose of 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 is 300mg on the day of start of administration and 150mg on and after the second day of administration, in terms of a free form.

The dose of 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 hydrochloride is preferably 300mg on the day of the start of the administration and 150mg on and after the second day of the administration. Here, the dose indicates a value obtained by converting 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 hydrochloride into a free form.

The pharmaceutically acceptable salt may be used in the form of a pharmaceutically acceptable salt of 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. Examples of the 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 is particularly preferable.

"free form" means 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 which is neither a salt, a co-crystal nor a hydrate and is of C₂₁H₂₄F₃N₃O₄Compound of formula (iii) and having a molecular weight of 439.44.

The therapeutic agent of the present embodiment may be constituted only of 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 as an active ingredient. Alternatively, the therapeutic agent of the present embodiment may be constituted as a pharmaceutical composition containing 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 other compounds and/or pharmaceutically acceptable additives serving as an active ingredient.

The pharmaceutical composition may contain one or more compounds as further compounds acting as active ingredients and/or pharmaceutically acceptable additives. For example, a pharmaceutical composition is prepared by mixing 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 with one or more of other compounds and additives serving as active ingredients.

As described above, according to the present embodiment, there can be provided a technique relating to a therapeutic agent having a high therapeutic effect and safety against aspiration pneumonia, lung suppuration, or lung abscess. By using an appropriate composition as described herein, a sufficient therapeutic effect can be obtained even when a small dose is used, while reducing side effects and reducing the frequency of occurrence of drug-resistant bacteria.