CN116549446A - 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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- CN116549446A CN116549446A CN202310755318.XA CN202310755318A CN116549446A CN 116549446 A CN116549446 A CN 116549446A CN 202310755318 A CN202310755318 A CN 202310755318A CN 116549446 A CN116549446 A CN 116549446A
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- fluoropyrrolidin
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Classifications
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- 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
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- 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
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- 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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a therapeutic agent for aspiration pneumonia, lung suppuration or lung abscess. The present invention relates to a safer and more effective therapeutic agent for respiratory tract infection. [ solution ] 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.
Description
The present application is a divisional application of application number "201880039674.9", entitled "therapeutic agent for aspiration pneumonia, lung suppuration or lung abscess".
Technical Field
The present invention relates to a therapeutic agent for aspiration pneumonia, lung suppuration or lung abscess.
Background
Quinolone carboxylic acid antibacterial agents called new quinolones have been developed worldwide since the development of norfloxacin, and many new quinolone antibacterial agents are now widely used as therapeutic drugs for infectious diseases.
Meanwhile, a quinolone carboxylic acid derivative represented by the general formula (1) has been disclosed by the applicant (patent document 1).
[1]
In the formula (1), R 1 Represents an alkyl group having 1 to 6 carbon atoms optionally substituted by 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 with one or more identical or different substituents selected from halogen atoms and amino groups; r is R 2 Represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or a pharmaceutically acceptable cation; r is R 3 Represents a hydrogen atom, a halogen atom, a hydroxyl group, an amino group or an alkyl group having 1 to 3 carbon atoms; r is R 4 Represents a hydrogen atom or a halogen atom; r is R 5 Represents a fluorine atom; r is R 6 Represents 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- [ (3 s,4 s) -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 carbostyril carboxylic acid derivatives described above. Further, a hydrochloride thereof is disclosed in patent document 2.
In addition, one example of respiratory tract infections includes aspiration pneumonia. Aspiration pneumonia is a disease that accounts for most of pneumonia in elderly people, 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 enterobacteria (non-patent document 1), but methods for effectively treating aspiration pneumonia have not been established so far. The quinolone formulations currently commercially available include levofloxacin, ciprofloxacin, pazufloxacin, moxifloxacin, sitafloxacin, and ganaxacin. For aspiration pneumonia, which is a highly serious disease, most of the initial treatments use injectable formulations, but among the above-mentioned quinolone formulations, levofloxacin, ciprofloxacin, and pazufloxacin, which give injectable formulations thereof, are available for insufficient antibacterial activity against anaerobic bacteria, and are not recommended for use in patients suspected of having aspiration pneumonia (non-patent document 2). In oral formulations, sitafloxacin, moxifloxacin and ganaxoxacin may be effective against anaerobic bacterial infections (non-patent documents 3 to 5), but papers with strong evidence for aspiration pneumonia have not been reported, and effective treatment methods have 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 observing therapeutic efficacy against moxifloxacin and pazufloxacin (non-patent documents 3 to 4 and non-patent document 7), they have not been established as effective therapeutic methods so far.
Reference list
Non-patent literature
Non-patent document 1: japanese society of medicine, , no. 99, 11, 10, 2010, pages 2746-2751.
Non-patent document 2: the Japanese society of respirators of French society, medicine for treating pneumonia by treating kidney-spleen in connection with lung disease to page 23 of the space.
Non-patent document 3: infection (Munich, germany) (2008), 36 (1), 23-30.
Non-patent document 4: expert Review of Respiratory Medicine (2007), 1 (1), 111-119.
Non-patent document 5: general society, the institute of respiratory in japan, division of adult pneumonia, page 24 of division 2017.
Non-patent document 6: japanese society of respirators ,49 (9): 623-628, 2011.
Non-patent document 7: nippon Kagaku Ryoho Gakkai Zasshi (1999), 47 (journal 1), 196-203.
Patent literature
Patent document 1: WO 2005/026147 booklet
Patent document 2: international publication No. WO 2013/069297
Summary of The Invention
Technical problem
It is an object of the present invention to provide novel therapeutic agents for respiratory tract infections.
Solution to the problem
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- [ (3 s,4 s) -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- [ (3 s,4 s) -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 comprising 7- [ (3 s,4 s) -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- [ (3 s,4 s) -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 bacteria of aspiration pneumonia, lung suppuration or lung abscess are one or more bacteria selected from the group consisting of: bacteria belonging to the genus Prevolella (Prevolella), bacteria belonging to the genus Streptococcus (Peptostreptococcus), bacteria belonging to the genus Micromonad (Parvimonas), bacteria belonging to the genus peptone bacteria (Peptoniphilus), bacteria belonging to the genus Fineldella (Finelgoldia) and bacteria belonging to the genus 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 Prevolella (Prevolella), bacteria belonging to the genus Streptococcus (Peptostreptococcus), bacteria belonging to the genus Micromonad (Parvimonas), bacteria belonging to the genus peptone bacteria (Peptoniphilus), bacteria belonging to the genus Fineldella (Finelgoldia) and bacteria belonging to the genus Fusobacterium.
[6] The therapeutic agent according to [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 Prevolella (Prevolella), bacteria belonging to the genus Streptococcus (Peptostreptococcus), bacteria belonging to the genus Micromonad (Parvimonas), bacteria belonging to the genus peptone bacteria (Peptoniphilus), bacteria belonging to the genus Fineldella (Finelgoldia) and bacteria belonging to the genus Fusobacterium.
[7] The therapeutic agent according to [1], wherein the pathogenic bacteria of aspiration pneumonia, lung suppuration or lung abscess are one or more bacteria selected from the group consisting of: bacteria belonging to the genus Bacteroides (bacteria), bacteria belonging to the genus Prevotella (Prevotella), bacteria belonging to the genus Porphyromonas (Porphyromonas), bacteria belonging to the genus Fusobacterium (Fusobacter), bacteria belonging to the genus ciliated (Leptotrichia), bacteria belonging to the genus Peptostreptococcus (Peptostreptococcus), bacteria belonging to the genus Micromonad (Parvimomonas), bacteria belonging to the genus Vellonella (Vellonella), bacteria belonging to the genus Thai (Tissierella), streptococcus angina (Streptococcus anginosus), and bacteria belonging to the genus 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 (bacteria), bacteria belonging to the genus Prevotella (Prevotela), bacteria belonging to the genus Micromonad (Parvimonas), bacteria belonging to the genus Weironella (Veilonella) and bacteria belonging to the genus Actinomyces.
[9] The therapeutic agent according to [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), bacteria belonging to the genus Prevobacteria (Prevobacteria), bacteria belonging to the genus Porphyromonas (Porphyromonas), bacteria belonging to the genus Fusobacterium (Fusobacteria), bacteria belonging to the genus ciliated (Leptotrichia), bacteria belonging to the genus Peptostreptococcus (Peptostreptococcus), bacteria belonging to the genus Micromonad (Parvimonas), bacteria belonging to the genus Vellonella (Vellonella), bacteria belonging to the genus Thai (Tissierella) and the group Streptococcus angina (Streptococcus anginosus).
[10] The therapeutic agent according to [1], wherein a 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, 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, calculated as 7- [ (3S, 4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof is 300mg at the beginning day of administration and 150mg at the second day and after administration.
[11] The therapeutic agent according to [2], wherein a 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, 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, calculated as 7- [ (3S, 4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable salt thereof is 300mg at the beginning day of administration and 150mg at the second day and after 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, calculated as 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 at the beginning of administration and 150mg at the second day and after administration.
Advantageous effects of the invention
According to the present invention, there is provided a therapeutic agent for aspiration pneumonia, lung suppuration or lung abscess, which comprises administering 7- [ (3 s,4 s) -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, and particularly relates to a therapeutic agent for respiratory infections. More specifically, the therapeutic agents of this embodiment are directed to therapeutic agents for aspiration pneumonia, lung suppuration or lung abscess, which comprise administering 7- [ (3 s,4 s) -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 humans.
Respiratory tract infections refer to infections that occur anywhere in the respiratory tract. In addition, the respiratory tract is a generic term for respiratory-related organs 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 disorder that includes lung and airway swelling and infection, and is thought to be caused by aspiration of harmful substances. Patients with aspiration pneumonia may have symptoms such as cough and dyspnea.
In this context, a patient suffering from aspiration pneumonia means a person meeting the following criteria:
clear invasive shadows of acute appearance are observed on chest X-ray or CT images.
Clear inhalation has been confirmed, recurrent air peduncles have been confirmed, dysfunction has been confirmed in a swallowing function assessment test, or the patient has a disease complication or history of possible dysphagia.
Patients show symptoms and inflammation characteristic of aspiration pneumonia.
Cough, purulent sputum, moist heat, dyspnea, fever, CRP positive, leukocytosis, hypoxia, etc. are exemplified as the characteristic symptoms and inflammation of aspiration pneumonia.
As used herein, a "lung suppuration" is a necrotic lung infection, also known as a lung abscess, and is thought to be caused by inhalation of bacteria in the mouth and throat into the lung. Patients suffering from lung suppuration may have symptoms such as fatigue, loss of appetite, sweating, fever, weight loss, and cough with phlegm.
In this context, a patient suffering from lung suppuration means a person meeting the following criteria:
a block shadow or a shadow with a void inside (a nodule shadow, a lump shadow) is observed on the chest X-ray or CT image. (irrespective of the presence or absence of a gas-liquid plane (niveau) due to pus accumulation.)
Patients show symptoms and inflammation characteristic of lung suppuration/lung abscess.
Cough, purulent sputum, moist heat, dyspnea, fever, CRP positive, leukocytosis, hypoxia, etc. are exemplified as the characteristic symptoms and inflammation of lung suppuration or lung abscess.
Finding a safe and effective compound against anaerobic pathogens is important for effective treatment of diseases such as aspiration pneumonia, lung suppuration or lung abscess. 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 pharmaceutically acceptable salts thereof are effective against anaerobic pathogens, unlike other quinolone compounds. For example, it is considered that an injection of a quinolone compound such as levofloxacin, ciprofloxacin, or pazufloxacin is not suitable 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 pathogens and 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 anaerobe, which is a pathogenic bacterium of aspiration pneumonia, lung suppuration or lung abscess, includes a bacterium belonging to the genus Bacteroides (bacteriodes), a bacterium belonging to the genus Prevotella (Prevotelella), a bacterium belonging to the genus Porphyromonas (Porphyromonas), a bacterium belonging to the genus Fusobacteria (Fusobacteria), a bacterium belonging to the genus Cellomyces (Leptotrichia), a bacterium belonging to the genus Streptococcus (Peptostreptococcus), a bacterium belonging to the genus Micromonas (Parvimonas), a bacterium belonging to the genus Wegrococcus (Veilonella), a bacterium belonging to the genus Tatariella (Tissierella), a bacterium belonging to the genus Peptophililus (Peptoiphilus) and a bacterium belonging to the genus Finelgildinia, and the group Streptococcus (Streptococcus anginosus) including a bacterium belonging to the genus Streptococcus (Streptococcus) and 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 high antibacterial activity against the anaerobic bacteria described above and exhibits high therapeutic effect against aspiration pneumonia, lung suppuration or lung abscess.
Examples of pathogenic bacteria of aspiration pneumonia include bacteria belonging to the genus Prevolella (Prevolella), bacteria belonging to the genus Peptostreptococcus (Peptostreptococcus), bacteria belonging to the genus Micromonad (Parvimonas), bacteria belonging to the genus Peptophaophilus (Peptophilius), bacteria belonging to the genus Fineldella (Finelgoldia), bacteria belonging to the genus Fusobacterium, bacteria belonging to the genus Bacteroides (Bacteroides) and bacteria belonging to the genus Streptococcus (Streptomyces).
Regarding the treatment of aspiration pneumonia, particularly when the pathogenic bacteria of aspiration pneumonia are the following, 7- [ (3 s,4 s) -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 Bacteroides (bacteria), bacteria belonging to the genus Prevotella (Prevotela), bacteria belonging to the genus Micromonad (Parvimonas), bacteria belonging to the genus Weironella (Veilonella) or bacteria belonging to the genus 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 Pseudomonas, bacteria belonging to the genus Peptophaga, bacteria belonging to the genus Peptophacophilus, bacteria belonging to the genus Finelgildium, bacteria belonging to the genus Clostridium, bacteria belonging to the genus Bacteroides and bacteria belonging to the genus Streptococcus.
Regarding the treatment of lung suppurations or lung abscesses, particularly when the pathogenic bacteria of the lung suppurations or lung abscesses are the following, 7- [ (3 s,4 s) -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 Prevotela, bacteria belonging to the genus Porphyromonas (Porphyromonas), bacteria belonging to the genus Fusobacterium, bacteria belonging to the genus Cellobacter (Leptotrichia), bacteria belonging to the genus Peptostreptococcus, bacteria belonging to the genus Micromonospora, bacteria belonging to the genus Wellomonas (Vellonella), bacteria belonging to the genus Thielavia (Tissierella) or the group Streptococcus angina (Streptococcus anginosus).
Examples of bacteria belonging to the genus Prevopella include Prevobacteria (P.dentetica), prevobacteria (P.loeschii), prevobacteria melanogenesis (P.melanine), intermediate Prevobacteria (P.intemedia), blackened Prevobacteria (P.nigrescens), puvobacteria pallidum (P.palettes), pvobacteria (P.buccae), oral Prevobacteria (P.oris), oral Prevobacteria (P.buccalis), oral Prevobacteria (P.oralis), two-way Prevobacteria (P.bivia), lytic Prevobacteria (P.dis), pleurisPrevobacteria (P.pleuritis), preplerian (P.bergensis), meng Pulei Wo Jun (P.timentis) or P.naensis. From the viewpoint of therapeutic efficacy of 7- [ (3 s,4 s) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, more preferably, the case where the pathogenic bacteria of aspiration pneumonia is prasugrel melanogenesis (p.melaninogenica), intermediate prasuvorexa faciens (p.inter) or buccintay (p.buccae) and the case where the pathogenic bacteria of lung suppuration or lung abscess are prasuvorexa melanogenesis (p.melaninogenica), intermediate prasuvorexa facilis (p.inter) or oral prasuvorexa facilis (p.oralis) are mentioned.
Examples of bacteria belonging to the genus Streptococcus (Peptococcus) include anaerobic Streptococcus (P. Anaerobius) and stomatitis Streptococcus (P. Stomatis).
Examples of bacteria belonging to the genus Micromonad (Parvimonas) include Micromonad (P.micro). From the viewpoint of therapeutic efficacy of 7- [ (3 s,4 s) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, more preferably, the case where the pathogenic bacteria of aspiration pneumonia, lung suppuration or lung abscess is micro-monad (p.micro) is mentioned.
Examples of bacteria belonging to the genus peptophaga (peptonilus) include peptophaga saccharophila (Peptoniphilus asaccharolyticus), efuse peptophaga (Peptoniphilus ivorii), lacrimal peptophaga (Peptoniphilus lacrimalis) and halideophila (Peptoniphilus harei). From the viewpoint of therapeutic efficacy of 7- [ (3 s,4 s) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, more preferably, the case where the pathogenic bacteria of aspiration pneumonia, lung suppuration or lung abscess is saccharophaaccompanying bacterium (Peptoniphilus asaccharolyticus) is mentioned.
Examples of bacteria belonging to the genus Finelder (Finelgildia) include Dagella (Finelgildia magna). From the viewpoint of therapeutic efficacy of 7- [ (3 s,4 s) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, more preferably, the case where the pathogenic bacteria of aspiration pneumonia, lung suppuration or lung abscess is megafingoldbia magna is mentioned.
Examples of bacteria belonging to the genus Fusobacterium include Fusobacterium necroseum (f.necrophorum), fusobacterium nucleatum (f.clearum), fusobacterium mortiferum (f.mortiferum), and Fusobacterium proteus (f.varium). From the viewpoint of therapeutic efficacy of 7- [ (3 s,4 s) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, more preferably, a case is mentioned in which the pathogenic bacteria of lung suppuration or lung abscess is clostridium nucleatum (f.nucleic) or clostridium necrosicum (f.necropruum).
Examples of bacteria belonging to the genus Bacteroides (Bacteroides) include Bacteroides fragilis (B.fragilis), bacteroides thetaiotaomicron (B.thetaiotaomicron), bacteroides vulgare (B.vulgatus), bacteroides ovatus (B.ovatus), bacteroides simplex (B.uniformis), bacteroides elshii (B.eggerthii), B.nordii, B.salysersoae and Bacteroides mosaic (B.massileiensis). From the viewpoint of therapeutic efficacy of 7- [ (3 s,4 s) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, more preferably, the case where pathogenic bacteria for lung suppuration or lung abscess is bacteroides fragilis (b.freogiclis) is mentioned.
Examples of bacteria belonging to the genus Porphyromonas (Porphyromonas) include Porphyromonas gingivalis (P.gingivali), porphyromonas pulposus (P.endontis), porphyromonas nonsaccharolylis (P.asaccharolytica), porphyromonas lii (P.levii), and P.uenonis. From the viewpoint of therapeutic efficacy of 7- [ (3 s,4 s) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, more preferably, the case where pathogenic bacteria of lung suppuration or lung abscess is porphyromonas gingivalis (p.gingivalis) or porphyromonas pulposus (p.endodontis) is mentioned.
Examples of bacteria belonging to the genus ciliated (Leptotrichia) include oral ciliated (l.buccalis), ciliated herd (l.hofstadii), ciliated hong kong (l.hongkongensis), ciliated salva (l.shahii), ciliated goldfellovii (l.goodfellowii), ciliated tershi (l.trevisanii) and Wei De ciliated (l.wadei). From the viewpoint of therapeutic efficacy of 7- [ (3 s,4 s) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, more preferably, the case where the pathogenic bacteria of lung suppuration or lung abscess is oral ciliated (l.buccalis) is mentioned.
Examples of bacteria belonging to the genus Veillonella include Veillonella parvula (v. Parvula), atypical Veillonella (v. Attypica) and v. Montpellensis.
Examples of bacteria belonging to the genus Tai (Tissielella) include Tai-bacterium creatinine (T. Creatini), tai-bacterium creatinine (T. Creatini) and Tai-bacterium polar-tip (T. Praeacuta). From the viewpoint of therapeutic efficacy of 7- [ (3 s,4 s) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, more preferably, the case where pathogenic bacteria of lung suppuration or lung abscess is tehnia creatinine (t.creatini) is mentioned.
Examples of bacteria belonging to the group of Streptococcus angina (Streptococcus anginosus) include Streptococcus intermedius (S.intermedius) and Streptococcus constellation (S.constellation). From the viewpoint of therapeutic efficacy of 7- [ (3 s,4 s) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, more preferably, the case where pathogenic bacteria of lung suppuration or lung abscess are Streptococcus intermedium (S.inter.) and Streptococcus constellation (S.constellation) is mentioned.
Examples of bacteria belonging to the genus actinomycetes (actinomycetes) include actinomycetes European (A.europaeus), actinomycetes Qiao Ge (A.georgiae), actinomycetes gossypii (A.gerenceriae), actinomycetes Gracilii (A.graeventizii), actinomycetes chlamydia (A.israeli), actinomycetes michii (A.meyeri), actinomycetes naeslundii, actinomycetes neotame (A.neui), actinomycetes caries (A.odontolyticus), actinomycetes root (A.radicis), actinomycetes Ding Fangxian (A.radicinae), actinomycetes fraxinus (A.turicensis), actinomycetes genitalis (A.urogenitalis), actinomycetes viscosus (A.viscus) and actinomycetes (actinomycetes). From the viewpoint of therapeutic efficacy of 7- [ (3 s,4 s) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, the case where the pathogenic bacteria of aspiration pneumonia is actinomycetes of caries (a.odontolyticus) is more preferably mentioned.
Pathogenic bacteria are herein a concept that also includes bacteria that have acquired resistance. Drug resistance refers to a phenomenon in which an organism is resistant to a drug and the drug is or becomes less effective. Examples of resistance include resistance to penicillins, resistance to cephalosporins, resistance to carbapenems, resistance to aminoglycosides, resistance to macrolides, resistance to lincomycin, resistance to trimethoprim-sulfamethoxazole, resistance to tetracyclines, resistance to metronidazole, resistance to glycopeptides, resistance to oxazolidinones, resistance to daptomycin and resistance to quinolones.
Examples of pharmaceutically acceptable additives contained with 7- [ (3 s,4 s) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid in the above pharmaceutical composition include excipients, lubricants, binders, disintegrants, stabilizers, flavoring agents and diluents. These additives are not particularly limited as long as they can be used for preparing a pharmaceutical preparation, and those described in "medical drug additive dictionary (Japanese medical drug additive agent, japanese society of medical science (2007))" for example can be used as appropriate.
The therapeutic agents of this embodiment are administered to a subject, such as a human, by employing conventional pharmaceutically well-known forms and routes of administration. For example, formulations such as powders, tablets, capsules, fine granules, syrups, injections, ophthalmic solutions, aqueous nasal drops, aqueous ear drops or inhalation solutions may be orally administered or parenterally administered. That is, the therapeutic agents of this embodiment may be prepared by mixing the active ingredient with physiologically acceptable carriers, excipients, binders, diluents, and the like, for example, in the dosage form illustrated 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-hydroquinoline-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 compact formulation for easy administration, and preventing the occurrence of resistant bacteria. Further, the maximum daily dose preferably includes 300mg or less, 250mg or less, 200mg or less, and 175mg or less. Examples of daily dosages of 7- [ (3 s,4 s) -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 less, further preferably 100mg or more and 200mg less, further preferably 125mg or more and 175mg less, and particularly preferably 150mg. In the case of using a pharmaceutically acceptable salt of 7- [ (3 s,4 s) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, the value when converted to the free form is used as the daily dose described above. The dose for a day may be administered once or may be divided into 2 to 3 times (administrations), but is preferably administered once per day. In addition, if the effect is insufficient, a dose twice as large as the daily dose may be used.
Furthermore, loading administration is preferably performed so as to rapidly reach the target blood concentration. Loading administration means a design of administration that achieves a target blood concentration at an early stage by increasing the daily dose or the daily number of administrations at the initial stage of administration. The initial stage of administration means from day 1 to day 3 of the start of administration, preferably means from day 1 to day 2 of the start of administration, and further preferably means day 1 of the start of administration. In addition, as an increase in the daily dose, a double amount of the daily dose is preferably used.
In the case of carrying out loading administration, it is preferable to use twice the daily dose on the first day of starting administration. More preferred daily doses of 7- [ (3 s,4 s) -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, calculated as free form, are 300mg at the beginning of the administration and 150mg at the second and following days of administration.
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-carboxylate is preferably 300mg at the beginning of the administration and 150mg at and after the second day of administration. Here, the dosage represents 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-carboxylate into a free form.
The pharmaceutically acceptable salts may be used in the form of pharmaceutically acceptable salts of 7- [ (3 s,4 s) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-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 is particularly preferred.
"free form" means 7- [ (3S, 4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl]-6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydro-quinoline-3-carboxylic acid, which is neither a salt, co-crystal nor a hydrate, and is of C 21 H 24 F 3 N 3 O 4 A compound of the formula (la) and having a molecular weight of 439.44.
The therapeutic agent of this embodiment may consist solely of 7- [ (3 s,4 s) -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 agents of this embodiment may be formulated as pharmaceutical compositions containing 7- [ (3 s,4 s) -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 well as other compounds and/or pharmaceutically acceptable additives serving as active ingredients.
The pharmaceutical composition may contain one or more compounds as further compounds acting as active ingredients and/or pharmaceutically acceptable additives. Pharmaceutical compositions are prepared, for example, by mixing 7- [ (3 s,4 s) -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 the other compounds and additives serving as active ingredients.
As described above, according to the present embodiment, a technique involving a therapeutic agent having a high therapeutic effect and safety against aspiration pneumonia, lung suppuration or lung abscess can be provided. 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 occurrence frequency of drug-resistant bacteria.
Example (example)
Hereinafter, the present invention will be described in more detail by showing examples, but the scope of the present invention is not limited by these examples.
A150 mg injection 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 (hereinafter also referred to as "research new drug A") was prepared according to the method disclosed in International publication No. WO 2016/195014.
"150 mg" in 150mg of the injection indicates the weight in the case where 7- [ (3S, 4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylate is converted to the free form. In preparing the injection, 162.5mg (converted to free form: 150 mg) of 7- [ (3S, 4S) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylate was used. Test example 1 aspiration pneumonia
The investigation new drug a was intravenously administered to 13 subjects suspected of having aspiration pneumonia satisfying the following criteria for 7 to 14 days.
Age 16 years or older, clear invasive shadows of acute appearance were observed on chest X-ray or CT images taken 48 hours before the start of dosing.
Confirm clear inhalation, air stalk or dysphagia, with a disease or medical history that has the potential for dysphagia.
Patients show symptoms and inflammation characteristic of aspiration pneumonia.
Two doses of investigational new drug a (300 mg/day) were used the first day of dosing, and one dose of investigational new drug a (150 mg/day) was used the second day of dosing, followed by maintenance of the same dose (150 mg/day). The administration of the injections was performed intravenously over about 1 hour per dose.
Test example 2 lung suppuration or lung abscess
The investigation new drug a was intravenously administered to 11 subjects suspected of having lung suppuration or lung abscess satisfying the following criteria for 7 to 14 days.
Age 16 years or more, a massive shadow or a shadow with a void inside (nodule shadow, tumor shadow) was observed on chest X-ray or CT images taken 48 hours before the start of administration. Irrespective of the presence or absence of a gas-liquid plane (niveau) due to pus accumulation.
Patients present with symptoms and inflammation characteristic of lung suppuration or lung abscess.
Two doses of investigational new drug a (300 mg/day) were used the first day of dosing, and one dose of investigational new drug a (150 mg/day) was used the second day of dosing, followed by maintenance of the same dose (150 mg/day). The administration of the injections was performed intravenously over about 1 hour per dose.
The clinical efficacy of test examples 1 and 2 was determined by setting the following criteria based on the criteria for clinical efficacy against pneumonia described in the doctor's back size bed method (second edition) (Daiki Kai Ji 2012;60 (1): 30-45.9) for respiratory infections. The main evaluation item is the effectiveness of investigation of new drug A at the end or discontinuation of administration.
Herein, the end of administration means the evaluation day of the next day of the completion day of administration of the investigation new drug a. Further, the discontinuation time indicates the evaluation day carried out within 3 days from the last administration day or the discontinuation judgment day of the investigation of the new drug a. Furthermore, "at the end of administration or at the time of discontinuation" is expressed as the end of treatment (EOT). In addition, CRP is an abbreviation for C-reactive protein, and is one of acute phase reactants generated in a short time in response to various inflammations. It is a useful indicator for observing the effect of treatment because it increases in bacterial infections such as pneumonia over several hours and decreases rapidly as inflammation subsides.
Early drug efficacy assessment and end of treatment (EOT)
3 days after administration, the early drug efficacy assessment was judged according to table 1 as follows: "early treatment effect", "no early treatment effect" and "no judgment".
"early therapeutic effect" is defined as a case in which a significant improvement is observed 3 days after administration (regardless of whether administration is completed or continued after 4 days). In addition, in the case where CRP value and chest X-ray after 3 days of administration were not improved as compared with before starting administration, even if CRP or chest X-ray was not changed or deteriorated, it was judged that there was "early therapeutic effect" if clinical symptoms and body temperature had been improved.
If there is no change or deterioration in CRP or chest X-ray, and there is no change or improvement in clinical symptoms and body temperature, it is determined that there is no early therapeutic effect ", and safety of the subject is fully considered, and an investigator or the like makes appropriate decisions, such as suspending the clinical trial and switching to administration of other antibacterial drugs. Samples for microbiological evaluation were collected before starting the appropriate replacement antimicrobial treatment.
In addition, if the discontinuation day is the start of administration (day 0) or the next day of administration (day 1), then a determination of early drug efficacy is considered unnecessary. In the case of the third day (day 2) or later of administration, judgment is made using the test result at the time of suspension.
For end of treatment (EOT), clinical efficacy at end of dosing or discontinuation was determined according to table 1 in the following three stages: "valid", "invalid" and "not determinable". In the case where the treatment is suspended after the next day at the end of administration, the clinical efficacy at the end of administration is determined, and it is not necessary to determine the clinical efficacy at the time of suspension.
In addition, when the treatment is discontinued or when the research new drug is changed to a substitute antibacterial drug treatment after the end of its administration, it is judged as "ineffective". However, this does not apply to the case where at the end of treatment (EOT) is judged "effective" according to the criteria in table 1, even if modified to an alternative antibacterial treatment. In the case of a change to an alternative antibacterial therapy, in principle, a prescribed test, examination and judgment at the end of the therapy are made before the change.
TABLE 1
Table 1 early drug efficacy assessment and criteria at end of treatment
Tables 2 and 3 show the results of early drug efficacy assessment and treatment end in trial 1 and trial 2.
TABLE 2
TABLE 2 evaluation of early drug efficacy
TABLE 3
TABLE 3 at the end of treatment
The effective rate is a value obtained by the following formula.
Effective rate= (number of objects rated as "effective" divided by number of objects rated as "effective" or "ineffective") x 100 (%)
Tables 2 and 3 show that 7- [ (3 s,4 s) -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 has a high therapeutic effect on aspiration pneumonia, lung suppuration or lung abscess. In particular, the effective rate at the end of the treatment is remarkably high, with aspiration pneumonia of 100% and lung suppuration or lung abscess of 91%.
Tables 4 and 5 show the microbiological efficacy of test example 1 and test example 2 according to pathogenic bacteria.
TABLE 4
TABLE 4 microbiologic efficacy according to pathogenic bacteria (aspiration pneumonia)
TABLE 5
TABLE 5 microbiologic efficacy according to pathogenic bacteria (lung suppuration/lung abscess)
Tables 4 and 5 show that 7- [ (3 s,4 s) -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 has a high antibacterial effect against pathogenic bacteria of aspiration pneumonia, lung suppuration or lung abscess.
Industrial applicability
According to the present embodiment, it is possible to provide a therapeutic agent for aspiration pneumonia, lung suppuration or lung abscess, which is industrially useful.
Claims (12)
1. A therapeutic agent for aspiration pneumonia, lung suppuration or lung abscess, which comprises 7- [ (3 s,4 s) -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 comprising 7- [ (3 s,4 s) -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- [ (3 s,4 s) -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 of claim 1, wherein the pathogenic bacteria of aspiration pneumonia, lung suppuration or lung abscess are one or more bacteria selected from the group consisting of: bacteria belonging to the genus Prevotella, bacteria belonging to the genus Streptococcus, bacteria belonging to the genus Micromonad, bacteria belonging to the genus peptone, bacteria belonging to the genus Fingolde, and bacteria belonging to the genus Clostridium.
5. The therapeutic agent of claim 2, wherein the pathogenic bacteria of aspiration pneumonia is one or more bacteria selected from the group consisting of: bacteria belonging to the genus Prevotella, bacteria belonging to the genus Streptococcus, bacteria belonging to the genus Micromonad, bacteria belonging to the genus peptone, bacteria belonging to the genus Fingolde, and bacteria belonging to the genus Clostridium.
6. The therapeutic agent of claim 3, wherein the pathogenic bacteria of a lung suppuration or lung abscess are one or more bacteria selected from the group consisting of: bacteria belonging to the genus Prevotella, bacteria belonging to the genus Streptococcus, bacteria belonging to the genus Micromonad, bacteria belonging to the genus peptone, bacteria belonging to the genus Fingolde, and bacteria belonging to the genus Clostridium.
7. The therapeutic agent of claim 1, wherein the pathogenic bacteria of aspiration pneumonia, 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 Fusobacterium, bacteria belonging to the genus Cellostreptococcus, bacteria belonging to the genus Micromonospora, bacteria belonging to the genus Yu Weirong coccus, bacteria belonging to the genus Typhonium, the group of Streptococcus angina, and bacteria belonging to the genus Actinomyces.
8. The therapeutic agent of claim 2, wherein the pathogenic bacteria of aspiration pneumonia 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 Micromonad, bacteria belonging to the genus Yu Weirong coccus and bacteria belonging to the genus Actinomyces.
9. The therapeutic agent of claim 3, wherein the pathogenic bacteria of a 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 Fusobacterium, bacteria belonging to the genus Cellostreptococcus, bacteria belonging to the genus Streptococcus, bacteria belonging to the genus Micromonospora, bacteria belonging to the genus Yu Weirong coccus, bacteria belonging to the genus Typhonium and Streptococcus angina.
10. The therapeutic agent according to claim 1, wherein a daily dose of 7- [ (3 s,4 s) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, 7- [ (3 s,4 s) -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, calculated as 7- [ (3 s,4 s) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1, 2-fluoroethyl) -8-methoxy-4-dihydroquinoline-3-carboxylic acid, or a pharmaceutically acceptable salt thereof, is 300mg at the start day of administration and 150mg at the second day and after administration.
11. The therapeutic agent according to claim 2, wherein a daily dose of 7- [ (3 s,4 s) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, 7- [ (3 s,4 s) -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, calculated as 7- [ (3 s,4 s) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1, 4-dihydroquinoline-3-carboxylic acid, or a pharmaceutically acceptable salt thereof, is 300mg at the start of administration and 150mg at the second day and after administration.
12. The therapeutic agent according to claim 3, wherein a daily dose of 7- [ (3 s,4 s) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1- (2-fluoroethyl) -8-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid, 7- [ (3 s,4 s) -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, calculated as 7- [ (3 s,4 s) -3- { (cyclopropylamino) methyl } -4-fluoropyrrolidin-1-yl ] -6-fluoro-1, 4-dihydroquinoline-3-carboxylic acid, or a pharmaceutically acceptable salt thereof, is 300mg at the beginning day of administration and 150mg at the second day and after administration.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201762520961P | 2017-06-16 | 2017-06-16 | |
| US62/520961 | 2017-06-16 | ||
| JP2018-068159 | 2018-03-30 | ||
| JP2018068159 | 2018-03-30 | ||
| PCT/JP2018/022846 WO2018230686A1 (en) | 2017-06-16 | 2018-06-15 | Therapeutic agent for aspiration pneumonia, lung suppuration, or lung abscess |
| CN201880039674.9A CN110891571A (en) | 2017-06-16 | 2018-06-15 | Therapeutic agent for aspiration pneumonia, lung suppuration or lung abscess |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201880039674.9A Division CN110891571A (en) | 2017-06-16 | 2018-06-15 | Therapeutic agent for aspiration pneumonia, lung suppuration or lung abscess |
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| CN116549446A true CN116549446A (en) | 2023-08-08 |
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| CN202310755318.XA Pending CN116549446A (en) | 2017-06-16 | 2018-06-15 | Therapeutic agent for aspiration pneumonia, lung suppuration or lung abscess |
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| Country | Link |
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| KR (1) | KR20240096794A (en) |
| CN (1) | CN116549446A (en) |
| EA (1) | EA202090066A1 (en) |
| TW (1) | TW202415375A (en) |
| WO (1) | WO2018230686A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1653071A (en) * | 2002-03-18 | 2005-08-10 | 杏林制药株式会社 | 10-(3-cyclopropylaminomethyl-1-pyrrolidinyl)pyridobenzoxazinecarboxylic acid derivative effective against resistant bacterium |
| US20140288310A1 (en) * | 2011-11-10 | 2014-09-25 | Kyorin Pharmaceutical Co., Ltd | 7--6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid crystal |
| WO2016148066A1 (en) * | 2015-03-13 | 2016-09-22 | 杏林製薬株式会社 | Respiratory infection treating agent |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT1666477E (en) | 2003-09-10 | 2013-08-28 | Kyorin Seiyaku Kk | 7-(4-substituted 3- cyclopropylaminomethyl-1- pyrrolidinyl) q uinolonecarboxylic acid derivative |
| CA2987879A1 (en) | 2015-06-02 | 2016-12-08 | Kyorin Pharmaceutical Co., Ltd. | Aqueous drug |
-
2018
- 2018-06-15 TW TW112134781A patent/TW202415375A/en unknown
- 2018-06-15 CN CN202310755318.XA patent/CN116549446A/en active Pending
- 2018-06-15 WO PCT/JP2018/022846 patent/WO2018230686A1/en active Application Filing
- 2018-06-15 KR KR1020247019005A patent/KR20240096794A/en unknown
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1653071A (en) * | 2002-03-18 | 2005-08-10 | 杏林制药株式会社 | 10-(3-cyclopropylaminomethyl-1-pyrrolidinyl)pyridobenzoxazinecarboxylic acid derivative effective against resistant bacterium |
| US20140288310A1 (en) * | 2011-11-10 | 2014-09-25 | Kyorin Pharmaceutical Co., Ltd | 7--6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid crystal |
| WO2016148066A1 (en) * | 2015-03-13 | 2016-09-22 | 杏林製薬株式会社 | Respiratory infection treating agent |
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| Publication number | Publication date |
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| KR20240096794A (en) | 2024-06-26 |
| TW202415375A (en) | 2024-04-16 |
| WO2018230686A1 (en) | 2018-12-20 |
| EA202090066A1 (en) | 2020-04-15 |
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