WO1997007800A1 - Formes zwitterioniques de trovafloxacine - Google Patents

Formes zwitterioniques de trovafloxacine Download PDF

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Publication number
WO1997007800A1
WO1997007800A1 PCT/IB1996/000756 IB9600756W WO9707800A1 WO 1997007800 A1 WO1997007800 A1 WO 1997007800A1 IB 9600756 W IB9600756 W IB 9600756W WO 9707800 A1 WO9707800 A1 WO 9707800A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
hygroscopic
polymoφh
pentahydrate
pll
Prior art date
Application number
PCT/IB1996/000756
Other languages
English (en)
Inventor
Douglas John Meldrum Allen
David Bruning Joseph
Timothy Norris
Original Assignee
Pfizer Inc.
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
Priority to US09/011,725 priority Critical patent/US6066647A/en
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Priority to JP50343697A priority patent/JP3188476B2/ja
Priority to SK238-98A priority patent/SK23898A3/sk
Priority to RU98103873/04A priority patent/RU2144921C1/ru
Priority to AU63676/96A priority patent/AU704115B2/en
Priority to CA002229786A priority patent/CA2229786C/fr
Priority to BR9609998A priority patent/BR9609998A/pt
Priority to NZ312199A priority patent/NZ312199A/xx
Priority to IL12265196A priority patent/IL122651A/xx
Priority to EP96923020A priority patent/EP0850060A1/fr
Publication of WO1997007800A1 publication Critical patent/WO1997007800A1/fr
Priority to NO980862A priority patent/NO309814B1/no
Priority to MXPA/A/1998/001664A priority patent/MXPA98001664A/xx

Links

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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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 to the naphthyridone antibiotic trovafloxacin. More particularly, it relates to polymo ⁇ hs and the pentahydrate of the zwitterionic form of thereof having the formula I, below, and methods for their preparation. The invention further relates to methods of using, and pharmaceutical compositions comprising, the compounds of the invention for treatment of bacterial infections in mammals,-
  • trovafloxacin The zwitterionic forms of trovafloxacin are useful for the administration of the drug as a suspension.
  • a second embodiment of the invention relates to a process for preparing a zwitterion, of trovafloxacin, of the formula I which is selected from the group consisting of a non hygroscopic polymo ⁇ h PI, a hygroscopic polymo ⁇ h Pll and a pentahydrate thereof, as described above, comprising A. the steps of treating an aqueous suspension of a metastable form of the compound of the formula I
  • a process for preparing the metastable form of the zwitterion, of trovafloxacin, of the formula I by a) treating an acid salt of trovafloxacin with a base to raise the pH of the mixture to between 7.5 and 8.5 at an elevated temperature, removal of the mother liquor, washing the crystals with water and drying the crystals under vacuum at about 35 to about 40 °C; or b) treating a compound of the formula
  • A is hydrogen or an amine protecting group such as t-butyloxycarbonyl, benzyloxycarbonyl, (C,-C ⁇ )alkylcarbonyl and benzyl; and
  • a fourth embodiment of the invention provides a method of treating bacterial infections in a mammal which comprises administering to said mammal a bacterial infection treating effective amount of a compound of formula I as described above.
  • a composition for treating bacterial infections in a mammal which comprises a bacterial infection treating effective amount of a compound of formula I and a pharmaceutically acceptable carrier.
  • the present invention relates to a compound comprising a stable zwitterionic form of the antibiotic trovafloxacin of the formula
  • a compound of the formula I which is selected from a) a non hygroscopic first polymorph PI exhibiting the characteristic X-ray powder diffraction pattern described above; b) a hygroscopic second polymorph Pll exhibiting the characteristic
  • the invention also relates to processes for the preparation of the compounds of the formula I as illustrated in the following schemes.
  • a trovafloxacin salt I wherein X is an anion selected from those formed from mineral acids such as hydrochloric, sulfuric, nitric and phosphoric; organic acids such as sulfonic acids, e. g.
  • benzenesulfonic (besylic), p- toluenesulfonic (PTSA, tosylic), methanesulfonic (MSA, mesylic) and tnfluoromethanesulfonic (triflic); and carboxylic acids e.g., acetic, propnonic, benzoic, citric, tartaric, maleic, fumaric, succinic and malic, is converted to a metastable zwitterionic form 2 by raising the pH Of a slurry comprising compound i to a pH of between about 7.5 and 8.5 at a temperature ir ⁇ the ⁇ range of about 45 to about 55 °C using an aqueous basic solution.
  • carboxylic acids e.g., acetic, propnonic, benzoic, citric, tartaric, maleic, fumaric, succinic and malic
  • a preferred- salt is the mesylate.
  • the bases useful in the practice of this aspect of the invention include inorganic bases such as alkali or alkaline earth hydroxides, carbonates and bicarbonates and organic bases such as tri(C,-C ⁇ )alkyl amines, pyridine and morpholine.
  • a preferred aqueous base is saturated sodium bicarbonate.
  • the wet product is then dried to constant weight, in vacuo. at a temperature from about 35 to about 40°C.
  • compound 2 may be prepared directly from protected precursors 6, of the trovafloxacin salts i, of the formula
  • A is hydrogen or an amine protecting group such as t-butyloxycarbonyl, benzyloxycarbonyl, (C,-C ⁇ )alkylcarbonyl and benzyl; and
  • B is hydrogen or a carboxylic acid protecting group selected from benzyl, t-butyl and (C,-C ⁇ ) alkyl; with an amine and/or carboxylic acid deprotecting agent, respectively.
  • a preferred compound 6, wherein A is hydrogen and B is ethyl, is converted to compound 2 by treatment with a solution of NaOH in a polar solvent at an elevated temperature.
  • a preferred solvent is methanol and the temperature is the reflux temperature of the solvent.
  • the pH of the solution was then adjusted to between about 6.5 and 8.0 with dilute HCl and saturated aqueous NaHCO 3 was then added to adjust the pH to between about 7.5 and 8.5.
  • the product was recovered as indicated above.
  • Metastable trovafloxacin zwitterion 2 is converted to hygroscopic polymorph Pll, 4, by treatment with a non polar solvent such as -a hydrocarbon.
  • a preferred hydrocarbon is hexanes.
  • Residual water is removed azeotropically-and the product dried at about 35 to about 40 °C under vacuum.
  • Solvents useful for. the azeotropic removal of water traces include non-polar aliphatic hydrocarbons, such as hexanes and octanes, and aromatic hydrocarbons such as benzene and toluene.
  • Preferred solvents are the aliphatic hydrocarbons, most preferably hexanes.
  • Non hygroscopic polymo ⁇ h PI 3 can be prepared from compound 2 by treatment with a polar solvent followed by azeotropic removal of water and vacuum drying at about 30 to about 40° C.
  • Polar solvents useful for this conversion include
  • a preferred solvent is ethyl acetate.
  • compound 3 can be prepared from compound 4 by treating compound 4 with a refluxing polar solvent , as described above.
  • a preferred solvent is is ethyl acetate.
  • Compound 5 the pentahydrate of the compound of formula I, is prepared by air drying the wet crystals of compound i, at room temperature, until constant weight is achieved. Altematively, compound 5 may be prepared from compound 4 by treatment with water until a constant water uptake has been obtained. Compound 3 is not converted to compound 5 by exposure to water.
  • the antibacterial compounds of the invention i.e., polymo ⁇ h PI, polymorph Pll and the pentahydrate (hereafter lhe active compounds') are useful in the treatment of animals and humans having a broad spectrum of bacterial infections. They are particularly useful in treating gram-positive bacterial strains.
  • the active compounds may be administered alone, but will generally be administered in a mixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • they can be administered orally or in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents, in the case of animals, they are advantageously contained in an animal feed or drinking water in a concentration of about 5 to about 5000 ppm, preferably about 25 to about 500 ppm.
  • the compounds of formula I can be administered intramuscularly or subcutaneously at dosage levels of about 0.1 to about 50 mg/kg/day, advantageously about 0.2 to about 10 mg/kg/day given in a single daily dose or up to 3 divided doses.
  • the active compounds can be administered to humans, for the treatment of bacterial diseases by either oral or parenteral routes. They may be administered orally at dosage levels of about 0.1 to 500 mg/kg/day, advantageously 0.5-50 mg/kg/day given in a single dosage or up to 3 divided dosages. For intramuscular or intravenous administration, dosage levels are about 0.1-200 mg/kg/day, advantageously 0.5-50 mg/kg/day. While intramuscular administration may be a single dose or up to 3 divided doses, intravenous administration can include a continuous drip. Variations will necessarily occur depending on the weight and condition of the subject being treated and the particular route of administration chosen as will be known to those skilled in the art.
  • the active compounds may be administered alone, but will generally be administered in a mixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • they can be administered orally or in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents.
  • they are advantageously contained in an animal feed or drinking water in a concentration of about 5 to about 5000 ppm, preferably about 25 to about 500 ppm.
  • the compounds of formula I can be administered intramuscularly or subcutaneously at dosage levels of about 0.1 to about 50 mg/kg/day, advantageously about 0.2 to about 10 mg/kg/day given in a single daily dose or up to 3 divided doses.
  • the active compounds can be administered to humans by either oral or parenteral routes, and may be administered orally at dosage levels of about 0.1 to 500 mg/kg/day, advantageously 0.5-50 mg/kg/day given in a single dosage or up to 3 divided dosages.
  • dosage levels are about 0.1-200 mg kg/day, advantageously 0.5-50 mg/kg/day.
  • intramuscular administration may be a single dose or up to 3 divided doses
  • intravenous administration can include a continuous drip. Variations will necessarily occur depending on the weight and condition of the subject being treated and the particular route of administration chosen as will be known to those skilled in the art.
  • the antibacterial activity of the compounds of the invention is shown by testing according to the Steer's replicator technique which is a standard in vitro bacterial testing method described by E. Steers et al., Antibiotics and Chemotherapy, 9, 307 (1959).
  • the following examples illustrate the methods and compounds of the present invention. It will be understood, however, that the invention is not limited to the specific examples.
  • Example 1 Trovafloxacin zwitterion. metastable form A.
  • Trovafloxacin mesylate prepared according to Example 13B ofthe '402 patent) (20 g was stirred with demineralized water (100 mL). The crystal slurry was heated to about 50 °C and the slurry adjusted to a pH of about 8.0 by addition of saturated sodium bicarbonate solution. The slurry was held at about 50 °C for 30 minutes, allowed to cool to about 25 °C and stirred at this temperature for 30 minutes. The crystals were isolated by filtration and washed with demineralized water (27 mL).
  • the wet crystals were suspended in demineralized water (100 mL) and stirred for about 1 hour at about 50 °C, then cooled to about 20° C and stirred at this temperature for about 1 hour.
  • the crystals were filtered from the mother liquor, washed with demineralized water (about 27 mL) and dried to constant weight under vacuum at about 40 °C to yield the title product which contained 2.5 % residual water by analysis. Yield 16 .25 g, 97 %.
  • Trovafloxacin zwitterion polymorph PI (non hygroscopic form) Trovafloxacin mesylate, (75 g) was stirred with demineralised water (375 mL). The crystal slurry was heated to about 50 °C and the slurry adjusted to a pH of about 8.0 by addition of saturated sodium bicarbonate solution. The slurry was held at about 50 °C for 30 minutes, allowed to cool to about 25 °C and stirred at this temperature for 30 minutes. Crystals were isolated by filtration and washed with demineralised water (100 mL).
  • the wet crystals were suspended in demineralised water (375 mL) and stirred for 1 hour at about 50 °C, then cooled to about 20 °C and stirred at this temperature for about 1 hour.
  • the crystalline product was filtered from the mother liquor and washed with demineralised water (about 100 mL).
  • the wet crystals were stirred with ethyl acetate (1125 mL) and the resultant slurry heated to reflux and the water azeotropically removed.
  • the essentially anhydrous slurry was cooled to about 25 °C, the crystals were isolated by filtration and dried under vacuum at 40 °C until all the solvent had been removed to provide the title product. Yield 60 .9 g, 94 %.
  • the product is characterized by the X-ray powder diffraction pattern described above.
  • Example 3 Trovafloxacin zwitterion hygroscopic polymorph Pll
  • the title product of Example 1 , paragraph A, (5 g) was mixed with hexanes (150 mL) to form a slurry.
  • the slurry was heated to reflux and traces of residual water were removed azeotropically. After 4 hours at reflux the crystal slurry was cooled to about 25 °C, isolated by filtration and dried to constant weight under vacuum at about 40 °C. Yield 4.7 g, 94 %.
  • the title product was characterized by the X-ray powder diffraction pattern described above.
  • Trovafloxacin zwitterion pentahydrate Trovafloxacin mesylate (50 g) was stirred with demineralised water (250 mL). The crystal slurry was heated to 50 °C and the slurry adjusted to a pH of about 8.0 by addition of saturated sodium bicarbonate solution. The slurry was held at about 50 °C for 30 minutes, allowed to cool to about 25 °C and stirred at this temperature for 30 minutes. The crystals were isolated by filtration and washed with demineralised water (70 mL).
  • the wet crystals were suspended in demineralised water (250 mL) and stirred for 1 hour at about 50 °C, then cooled to about 20 °C and stirred at this temperature for about 1 hour.
  • the crystalline product was filtered from the mother liquor, washed with demineralised water (about 70 mL).
  • the wet crystals were air dried to constantnt weight at room temperature to yield the title product which contained 17.6 % water by analysis. Yield 48.4 g, 84 %
  • the title product was characterized by the X-ray powder diffraction pattern described above.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Physical Water Treatments (AREA)
  • Processing Of Solid Wastes (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

On décrit une forme zwittérionique de trovafloxacine possédant la formule (I) et choisie dans le groupe constitué par des polymorphes cristallins de celle-ci, hygroscopiques et non hygroscopiques, et par un pentahydrate de celle-ci. On décrit également des procédés de préparation de ces composés, des procédés d'utilisation de ceux-ci, ainsi que des compositions pharmaceutiques contenant ces composés et servant au traitement d'infections bactériennes chez les mammifères.
PCT/IB1996/000756 1995-08-29 1996-07-29 Formes zwitterioniques de trovafloxacine WO1997007800A1 (fr)

Priority Applications (12)

Application Number Priority Date Filing Date Title
CA002229786A CA2229786C (fr) 1995-08-29 1996-07-29 Formes zwitterioniques de trovafloxacine
JP50343697A JP3188476B2 (ja) 1995-08-29 1996-07-29 両性イオン形トロバフロキサシン
SK238-98A SK23898A3 (en) 1995-08-29 1996-07-29 Zwitterionic forms of trovafloxacin
RU98103873/04A RU2144921C1 (ru) 1995-08-29 1996-07-29 Кристаллическая форма цвиттериона тровафлоксацина и способ ее получения
AU63676/96A AU704115B2 (en) 1995-08-29 1996-07-29 Zwitterionic forms of trovafloxacin
US09/011,725 US6066647A (en) 1996-07-29 1996-07-29 Zwitterionic forms of trovafloxacin
BR9609998A BR9609998A (pt) 1995-08-29 1996-07-29 Formas zwitteriônicas de trovafloxacina
EP96923020A EP0850060A1 (fr) 1995-08-29 1996-07-29 Formes zwitterioniques de trovafloxacine
IL12265196A IL122651A (en) 1995-08-29 1996-07-29 Zwitterionic polymorphic forms of trovafloxacin their preparation and pharmaceutical compositions containing them
NZ312199A NZ312199A (en) 1995-08-29 1996-07-29 Zwitterionic forms of trovafloxacin
NO980862A NO309814B1 (no) 1995-08-29 1998-02-27 Zwitterionformer av trovafloxacin, fremgangsmÕte for fremstilling derav og preparat inneholdende disse
MXPA/A/1998/001664A MXPA98001664A (en) 1995-08-29 1998-02-27 Zwitterionic forms of trovafloxacin, procedure for its preparation, compositions that contain them and use of the mis

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US297595P 1995-08-29 1995-08-29
US60/002,975 1995-08-29

Publications (1)

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WO1997007800A1 true WO1997007800A1 (fr) 1997-03-06

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PCT/IB1996/000756 WO1997007800A1 (fr) 1995-08-29 1996-07-29 Formes zwitterioniques de trovafloxacine

Country Status (30)

Country Link
EP (1) EP0850060A1 (fr)
JP (1) JP3188476B2 (fr)
KR (1) KR100343909B1 (fr)
CN (1) CN1190889A (fr)
AP (1) AP636A (fr)
AR (1) AR003985A1 (fr)
AU (1) AU704115B2 (fr)
BR (1) BR9609998A (fr)
CA (1) CA2229786C (fr)
CO (1) CO4480739A1 (fr)
CZ (1) CZ56698A3 (fr)
DZ (1) DZ2087A1 (fr)
GT (1) GT199600072A (fr)
HR (1) HRP960395B1 (fr)
HU (1) HUP9900170A3 (fr)
IL (1) IL122651A (fr)
MA (1) MA23966A1 (fr)
MY (1) MY113874A (fr)
NO (1) NO309814B1 (fr)
NZ (1) NZ312199A (fr)
OA (1) OA10669A (fr)
PE (1) PE12598A1 (fr)
PL (1) PL325170A1 (fr)
RU (1) RU2144921C1 (fr)
SK (1) SK23898A3 (fr)
TN (1) TNSN96109A1 (fr)
TR (1) TR199800339T1 (fr)
WO (1) WO1997007800A1 (fr)
YU (1) YU48396A (fr)
ZA (1) ZA967282B (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0930068A2 (fr) * 1998-01-21 1999-07-21 Pfizer Products Inc. Comprimé contenant le trovafloxacine mesylate
EP0989119A1 (fr) * 1998-09-03 2000-03-29 Pfizer Products Inc. Procede et intermediaires destines a la preparation de sels d'acide trovafloxacincarboxylique
US6194429B1 (en) 1997-08-01 2001-02-27 Pfizer Inc Alatrofloxacin parenteral compositions
US6239141B1 (en) 1999-06-04 2001-05-29 Pfizer Inc. Trovafloxacin oral suspensions
KR100343356B1 (ko) * 1998-07-28 2002-07-15 실버스타인 아써 에이. 퀴놀론 및 나프티리돈 카복실산의 제조방법
US7019142B2 (en) 1998-01-16 2006-03-28 Pfizer Inc. Process for preparing naphthyridones and intermediates

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5164402A (en) * 1989-08-16 1992-11-17 Pfizer Inc Azabicyclo quinolone and naphthyridinone carboxylic acids

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5164402A (en) * 1989-08-16 1992-11-17 Pfizer Inc Azabicyclo quinolone and naphthyridinone carboxylic acids
US5229396A (en) * 1989-08-16 1993-07-20 Pfizer Inc. Anti-bacterial azabicyclo quinolone carboxylic acids

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6194429B1 (en) 1997-08-01 2001-02-27 Pfizer Inc Alatrofloxacin parenteral compositions
US7019142B2 (en) 1998-01-16 2006-03-28 Pfizer Inc. Process for preparing naphthyridones and intermediates
EP0930068A2 (fr) * 1998-01-21 1999-07-21 Pfizer Products Inc. Comprimé contenant le trovafloxacine mesylate
TR199900089A3 (tr) * 1998-01-21 1999-10-21 Pfizer Products Inc. Trovafloksasin mesilat tablet.
EP0930068A3 (fr) * 1998-01-21 1999-12-22 Pfizer Products Inc. Comprimé contenant le trovafloxacine mesylate
US6187341B1 (en) 1998-01-21 2001-02-13 Pfizer Inc. Trovafloxacin mesylate tablet
AP1094A (en) * 1998-01-21 2002-08-19 Pfizer Prod Inc Trovafloxacin mesylate tablet.
AU758381B2 (en) * 1998-01-21 2003-03-20 Pfizer Products Inc. Trovafloxacin mesylate tablet
KR100343356B1 (ko) * 1998-07-28 2002-07-15 실버스타인 아써 에이. 퀴놀론 및 나프티리돈 카복실산의 제조방법
EP0989119A1 (fr) * 1998-09-03 2000-03-29 Pfizer Products Inc. Procede et intermediaires destines a la preparation de sels d'acide trovafloxacincarboxylique
US6239141B1 (en) 1999-06-04 2001-05-29 Pfizer Inc. Trovafloxacin oral suspensions

Also Published As

Publication number Publication date
MX9801664A (es) 1998-08-30
DZ2087A1 (fr) 2002-07-22
AU6367696A (en) 1997-03-19
IL122651A0 (en) 1998-08-16
GT199600072A (es) 1998-02-14
BR9609998A (pt) 1999-07-06
KR100343909B1 (ko) 2003-04-10
HUP9900170A3 (en) 1999-11-29
HUP9900170A2 (hu) 1999-05-28
AP636A (en) 1998-04-09
NZ312199A (en) 1999-06-29
YU48396A (sh) 1998-12-23
CA2229786A1 (fr) 1997-03-06
TR199800339T1 (xx) 1998-06-22
MY113874A (en) 2002-06-29
PE12598A1 (es) 1998-03-20
KR19990044232A (ko) 1999-06-25
EP0850060A1 (fr) 1998-07-01
SK23898A3 (en) 1999-05-07
CA2229786C (fr) 2002-02-19
MA23966A1 (fr) 1997-04-01
NO980862D0 (no) 1998-02-27
NO309814B1 (no) 2001-04-02
CZ56698A3 (cs) 1999-02-17
JP3188476B2 (ja) 2001-07-16
TNSN96109A1 (fr) 2005-03-15
CN1190889A (zh) 1998-08-19
OA10669A (en) 2000-11-06
JPH10511692A (ja) 1998-11-10
AU704115B2 (en) 1999-04-15
AP9600853A0 (en) 1996-10-31
PL325170A1 (en) 1998-07-06
ZA967282B (en) 1998-03-02
NO980862L (no) 1998-02-27
RU2144921C1 (ru) 2000-01-27
CO4480739A1 (es) 1997-07-09
HRP960395A2 (en) 1998-06-30
IL122651A (en) 2000-02-17
HRP960395B1 (en) 2001-12-31
AR003985A1 (es) 1998-09-30

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