WO2002038156A2 - Procedes d'utilisation de composes de fluoroquinolone contre des bacteries pathogenes du genre helicobacter - Google Patents

Procedes d'utilisation de composes de fluoroquinolone contre des bacteries pathogenes du genre helicobacter Download PDF

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Publication number
WO2002038156A2
WO2002038156A2 PCT/US2001/047460 US0147460W WO0238156A2 WO 2002038156 A2 WO2002038156 A2 WO 2002038156A2 US 0147460 W US0147460 W US 0147460W WO 0238156 A2 WO0238156 A2 WO 0238156A2
Authority
WO
WIPO (PCT)
Prior art keywords
helicobacter
bacteria
gemifloxacin
pathogenic
pylori
Prior art date
Application number
PCT/US2001/047460
Other languages
English (en)
Other versions
WO2002038156A3 (fr
Inventor
Alison F. Chalker
Heather W. Minehart
Original Assignee
Smithkline Beecham Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to EP01985001A priority Critical patent/EP1337252A4/fr
Priority to JP2002540739A priority patent/JP2004513147A/ja
Priority to US10/416,179 priority patent/US20040023983A1/en
Priority to KR10-2003-7006239A priority patent/KR20030060928A/ko
Priority to AU2002233995A priority patent/AU2002233995A1/en
Publication of WO2002038156A2 publication Critical patent/WO2002038156A2/fr
Publication of WO2002038156A3 publication Critical patent/WO2002038156A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • This invention relates, in part, to newly identified methods of using quinolone antibiotics, particularly a gemifloxacin compound against Helicobacter bacteria, such as Helicobacter sp., H. pylori, and pathogenic species of Helicobacter.
  • Quinolones have been shown to be effective to varying degrees against a range of bacterial pathogens. However, as diseases caused by these pathogens are on the rise, there exists a need for antimicrobial compounds that are more potent than the present group of quinolones.
  • Gemifloxacin mesylate is a novel fluoroquinolone useful as a potent antibacterial agent.
  • Gemifloxacin compounds are described in detail in patent application PCT/KR98/00051 published as WO 98/42705.
  • Patent application EP 688772 discloses novel quinoline(naphthyridine)carboxylic acid derivatives, including anhydrous (R,S)-7-(3-aminomethyl-4-methoxyiminopyrrolidin-l-yl)-l-cyclopropyl- 6-fluoro-4-oxo-l,4-dihydro-l,8-naphthyridine-3-carboxylic acid of formula I.
  • PCT/KR98/00051 discloses (R,S)-7-(3-aminomethyl-4- 1 yyn-methoxyimino- pyrrolidin- 1 -yl)- 1 -cyclopropyl-6-fluoro-4-oxo- 1 ,4-dihydro- 1 ,8-naphthyridine-3- carboxylic acid methanesulfonate and hydrates thereof including the sesquihydrate.
  • a gemifloxacin compound against Helicobacter demonstrating the activity of the gemifloxacin compound used was superior to a number of quinolones as described in more detail herein.
  • Gemifloxacin compounds are valuable compounds for the treatment of bacterial infection caused by a range of Helicobacter pathogens, including those resistant to usual oral therapy, thereby filling an unmet medical need.
  • An object of the invention is a method for modulating metabolism of pathogenic Helicobacter bacteria comprising the step of contacting pathogenic Helicobacter bacteria with an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound, or an antibacterially effective derivative thereof.
  • a further object of the invention is a method wherein said pathogenic Helicobacter bacteria is selected from the group consisting of: members of the genus Helicobacter, Helicobacter sp, H pylori, and a pathogenic species of Helicobacter.
  • a method of treating or preventing a bacterial infection by pathogenic Helicobacter bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal suspected of having or being at risk of having an infection with pathogenic Helicobacter bacteria.
  • a preferred method is provided wherein said modulating metabolism is inhibiting growth of said bacteria or killing said bacteria.
  • a further preferred method is provided wherein said contacting said bacteria comprises the further step of introducing said composition into a mammal, particularly a human.
  • said bacteria is selected from the group consisting of: members of the genus Helicobacter, Helicobacter sp, H. pylori, and a pathogenic species of Helicobacter.
  • the preferred composition of the invention include, among other things, methods wherein said composition comprises gemifloxacin, or a pharmaceutically acceptable derivative thereof.
  • the invention also provides methods wherein the gemifloxacin compound is gemifloxacin or a pharmaceutically acceptable salt thereof, or a gemifloxacin compound such as gemifloxacin mesylate or a hydrate thereof, and/or the gemifloxacin compound is gemifloxacin mesylate sesquihydrate.
  • the present invention provides, among other things, methods for using a composition comprising a quinolone, particularly a gemifloxacin compound against a range of pathogenic bacteria.
  • gemifloxacin compound(s) means a compound having antibacterial activity described in patent application PCT/KR98/00051 published as WO 98/42705, or patent application EP 688772.
  • This invention was based, in part, on analyses evaluating the in vitro activity of a gemifloxacin compound, as well as other new quinolones using low-passaged clinical isolates and type strains of Helicobacter species commonly found in the gastrointestinal tract of humans.
  • Organisms used in the analyses included : members of the genus Helicobacter, Helicobacter sp, H. pylori, and a pathogenic species of Helicobacter.
  • H. pylori The common gastric pathogen Helicobacter pylori is implicated in the development of chronic gastritis, duodenal and gastric ulcers and gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and there is an established link between H. pylori infection and gastric cancer. Eradication of the infection is often recommended for symptomatic H. /ry/ ⁇ rz ' -positive patients, particularly those with duodenal or gastric ulcer. However, the efficacy of common triple therapy treatments for H pylori is being undermined by the rise in frequency of antibiotic resistant isolates.
  • the aim of the present invention is to evaluate the susceptibility of H. pylori to the new fluoroquinolone gemifloxacin (SB-265805).
  • Twenty-one (21) H. pylori strains were obtained, including 16 clinical isolates CCUG 39297, CCUG 30988 (Lelwala- Guruge, J., Ljungh, A., & Wadstrom, T. 1992.
  • APMIS 100, 908-13 CCUG 17875 (Lelwala-Guruge, J., Ljungh, A., & Wadstrom, T. 1992.
  • APMIS 100, 908-13 liver, D., Arnqvist, A., Ogren, J., Frick, I.
  • comparator drugs to which gemifloxacin was compared, include levofloxacin, ciprofloxacin, moxifloxacin and gatifloxacin.
  • the activities of amoxycillin, tetracycline and metronidazole against H. pylori ATCC 43504 were also tested as controls.
  • the agar plates were inoculated using a Steers replicator and read at 72 hours.
  • the invention provides a method for modulating metabolism of pathogenic Helicobacter bacteria. Skilled artisans can readily choose pathogenic Helicobacter bacteria or patients infected with or suspected to be infected with these organisms to practice the methods of the invention. Alternatively, the bacteria useful in the methods of the invention may be those described herein.
  • the contacting step in any of the methods of the invention may be performed in many ways that will be readily apparent to the skilled artisan. However, it is preferred that the contacting step is a provision of a composition comprising a gemifloxacin compound to a human patient in need of such composition or directly to bacteria in culture medium or buffer.
  • compositions comprising a quinolone, particularly a gemifloxacin compound may be administered in any effective, convenient manner including, for instance, administration by topical, oral, anal, vaginal, intravenous, intraperitoneal, intramuscular, subcutaneous, intranasal or intradermal routes among others.
  • compositions be employed in combination with a non-sterile or sterile carrier or carriers for use with cells, tissues or organisms, such as a pharmaceutical carrier suitable for administration to a subject.
  • a pharmaceutical carrier suitable for administration to a subject comprise, for instance, a media additive or a therapeutically effective amount of a compound of the invention, a quinolone, preferably a gemifloxacin compound, and a pharmaceutically acceptable carrier or excipient.
  • Such carriers may include, but are not limited to, saline, buffered saline, dextrose, water, glycerol, ethanol and combinations thereof. The formulation should suit the mode of administration.
  • Quinolone compounds particularly gemifloxacin compounds and compostions of the methods of the invention may be employed alone or in conjunction with other compounds, such as bacterial efflux pump inhibitor compounds or antibiotic compounds, particularly non-quinolone compounds, e.g., beta-lactam antibiotic compounds.
  • the active agent of a method of the invention is preferably administered to an individual as an injectable composition, for example as a sterile aqueous dispersion, preferably an isotonic one.
  • the gemifloxacin compounds or compositions in the methods of the invention may be formulated for topical application for example in the form of ointments, creams, lotions, eye ointments, eye drops, ear drops, mouthwash, impregnated dressings and sutures and aerosols, and may contain appropriate conventional additives, including, for example, preservatives, solvents to assist drug penetration, and emollients in ointments and creams.
  • Such topical formulations may also contain compatible conventional carriers, for example cream or ointment bases, and ethanol or oleyl alcohol for lotions.
  • suitable conventional carriers for example cream or ointment bases, and ethanol or oleyl alcohol for lotions.
  • Such carriers may constitute from about 1% to about 98% by weight of the formulation; more usually they will constitute up to about 80% by weight of the formulation.
  • the antibacterially effective amount is a daily dosage level of the active agent from 0.001 mg/kg to 10 mg/kg, typically around 0.1 mg/kg to 1 mg/kg, preferably about 1 mg/kg.
  • a physician in any event, will determine an actual dosage that is most suitable for an individual and will vary with the age, weight and response of the particular individual. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention. It is preferred that the dosage is selected to modulate metabolism of the bacteria in such a way as to inhibit or stop growth of said bacteria or by killing said bacteria.
  • a further embodiment of the invention provides for the contacting step of the methods to further comprise contacting an in-dwelling device in a patient.
  • Indwelling devices include, but are not limited to, surgical implants, prosthetic devices and catheters, i.e., devices that are introduced to the body of an individual and remain in position for an extended time.
  • Such devices include, for example, artificial joints, heart valves, pacemakers, vascular grafts, vascular catheters, cerebrospinal fluid shunts, urinary catheters, and continuous ambulatory peritoneal dialysis (CAPD) catheters.
  • CAPD continuous ambulatory peritoneal dialysis
  • a quinolone, particularly a gemifloxacin compound or composition of the invention may be administered by injection to achieve a systemic effect against relevant bacteria, preferably a pathogenic Helicobacter bacteria, shortly before insertion of an in-dwelling device. Treatment may be continued after surgery during the in-body time of the device.
  • the composition could also be used to broaden perioperative cover for any surgical technique to prevent bacterial wound infections caused by or related to pathogenic Helicobacter bacteria.
  • a gemifloxacin compound or composition used in the methods of this invention may be used generally as a wound treatment agent to prevent adhesion of bacteria to matrix proteins, particularly pathogenic Helicobacter bacteria, exposed in wound tissue and for prophylactic use in dental treatment as an alternative to, or in conjunction with, antibiotic prophylaxis.
  • a quinolone, particularly a gemifloxacin compound or composition of the invention may be used to bathe an indwelling device immediately before insertion.
  • the active agent will preferably be present at a concentration of l ⁇ g/ml to lOmg/ml for bathing of wounds or indwelling devices.
  • a method of treating or preventing a bacterial infection by pathogenic Helicobacter bacteria comprising the step of administering an antibacterially effective amount of a composition comprising a quinolone, particularly a gemifloxacin compound to a mammal, preferably a human, suspected of having or being at risk of having an infection with pathogenic Helicobacter bacteria.
  • While a preferred object of the invention provides a method wherein said pathogenic Helicobacter bacteria is selected from the group consisting of : Helicobacter sp., H. pylori, and pathogenic species of Helicobacter. Other pathogenic Helicobacter bacteria may also be included in the methods. The skilled artisan may identify these organisms as provided herein as well as using other methods known in the art, e.g. MIC tests.
  • the preferred composition of the invention include, among other things, methods wherein said composition comprises gemifloxacin, or a pharmaceutically acceptable derivative thereof.
  • the invention also provides methods wherein the gemifloxacin compound is gemifloxacin or a pharmaceutically acceptable salt thereof, or a gemifloxacin compound such as gemifloxacin mesylate or a hydrate thereof, and/or the gemifloxacin compound is gemifloxacin mesylate sesquihydrate.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne en partie des procédés identifiés récemment servant à utiliser des antibiotiques à base de quinolone, en particulier, un composé de gémifloxacine contre certaines bactéries pathogènes.
PCT/US2001/047460 2000-11-10 2001-11-08 Procedes d'utilisation de composes de fluoroquinolone contre des bacteries pathogenes du genre helicobacter WO2002038156A2 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP01985001A EP1337252A4 (fr) 2000-11-10 2001-11-08 Procedes d'utilisation de composes de fluoroquinolone contre des bacteries pathogenes du genre helicobacter
JP2002540739A JP2004513147A (ja) 2000-11-10 2001-11-08 病原性ヘリコバクター細菌に対するフルオロキノロン化合物の使用方法
US10/416,179 US20040023983A1 (en) 2001-11-08 2001-11-08 Methods of use of fluoroquinolone compounds against pathogenic helicobacter bacteria
KR10-2003-7006239A KR20030060928A (ko) 2000-11-10 2001-11-08 병원성 헬리코박터 박테리아에 대한 플루오로퀴놀론화합물의 사용방법
AU2002233995A AU2002233995A1 (en) 2000-11-10 2001-11-08 Methods of use of fluoroquinolone compounds against pathogenic helicobacter bacteria

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US24709300P 2000-11-10 2000-11-10
US60/247,093 2000-11-10

Publications (2)

Publication Number Publication Date
WO2002038156A2 true WO2002038156A2 (fr) 2002-05-16
WO2002038156A3 WO2002038156A3 (fr) 2002-07-11

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PCT/US2001/047460 WO2002038156A2 (fr) 2000-11-10 2001-11-08 Procedes d'utilisation de composes de fluoroquinolone contre des bacteries pathogenes du genre helicobacter

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EP (1) EP1337252A4 (fr)
JP (1) JP2004513147A (fr)
KR (1) KR20030060928A (fr)
AU (1) AU2002233995A1 (fr)
WO (1) WO2002038156A2 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6262071B1 (en) * 1999-06-29 2001-07-17 Smithkline Beecham Corporation Methods of use of antimicrobial compounds against pathogenic amycoplasma bacteria
US6331550B1 (en) * 1999-06-29 2001-12-18 Smithkline Beecham Corporation Methods of use of quinolone compounds against anaerobic pathogenic bacteria
US6340689B1 (en) * 1999-06-29 2002-01-22 Smithkline Beecham Corporation Methods of use of quinolone compounds against atypical upper respiratory pathogenic bacteria

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH11209286A (ja) * 1998-01-21 1999-08-03 Kyorin Pharmaceut Co Ltd ガチフロキサシンを有効成分とする抗Ｈ．ｐｙｌｏｒｉ剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6262071B1 (en) * 1999-06-29 2001-07-17 Smithkline Beecham Corporation Methods of use of antimicrobial compounds against pathogenic amycoplasma bacteria
US6331550B1 (en) * 1999-06-29 2001-12-18 Smithkline Beecham Corporation Methods of use of quinolone compounds against anaerobic pathogenic bacteria
US6340689B1 (en) * 1999-06-29 2002-01-22 Smithkline Beecham Corporation Methods of use of quinolone compounds against atypical upper respiratory pathogenic bacteria

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1337252A2 *

Also Published As

Publication number Publication date
EP1337252A4 (fr) 2005-06-22
EP1337252A2 (fr) 2003-08-27
KR20030060928A (ko) 2003-07-16
JP2004513147A (ja) 2004-04-30
WO2002038156A3 (fr) 2002-07-11
AU2002233995A1 (en) 2002-05-21

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