CN1190889A - Zwitterionic forms of trovafloxacin - Google Patents
Zwitterionic forms of trovafloxacin Download PDFInfo
- Publication number
- CN1190889A CN1190889A CN96195624A CN96195624A CN1190889A CN 1190889 A CN1190889 A CN 1190889A CN 96195624 A CN96195624 A CN 96195624A CN 96195624 A CN96195624 A CN 96195624A CN 1190889 A CN1190889 A CN 1190889A
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- China
- Prior art keywords
- chemical compound
- polymorph
- removing dampness
- trovafloxacin
- pentahydrate
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Classifications
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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
-
- 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
Abstract
A zwitterionic form of trovafloxacin having formula (I) selected from the group consisting of its crystalline hygroscopic and non-hygroscopic polymorphs and pentahydrate 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.
Description
The present invention relates to naphthyridone class antibiotic trovafloxacin (trovafloxacin).More particularly, the present invention relates to the polymorph and the pentahydrate of zwitterionic form of the trovafloxacin of following formula I, and the method for preparing them.The invention still further relates to the using method and the pharmaceutical composition that comprises The compounds of this invention of The compounds of this invention, be used for the treatment of mammiferous bacterial infection.Above-mentioned patent and the application transfer the possession of together.
The antibiotic antibacterial activity of aforementioned naphthvridone class is in 11/17/92 and 7/20/93 U.S. Patent No. 5,164 of promulgation respectively, 402[' 402 patents] and 5,229,396 in put down in writing, their disclosure is introduced the present invention as a reference and fully.Above-mentioned patent and the application transfer the possession of together.
The zwitterionic form of trovafloxacin can use in the suspension administration.
First embodiment of the present invention provides the trovafloxacin of formula I amphion crystal form:
It is selected from:
A) show as the non-removing dampness first polymorph PI of following characteristic X-ray powder diffraction pattern
B) show as the removing dampness second polymorph PII of following characteristic X-ray powder diffraction pattern
And c) pentahydrate shows as the trovafloxacin amphion pentahydrate of following characteristic X-ray powder diffraction pattern
| Peak number | ??1 | ??2 | ??3 | ??4 | ??5 | ??6 | ??7 | ??8 | ??9 |
| ??2_θ_(°) ??Cu | ??6.9 | ??9.8 | ??11.3 | ??12.0 | ??13.9 | ??16.1 | ??16.6 | ??17.1 | ??17.4 |
| The d distance | ??12.7 | ??9.0 | ??7.9 | ??7.4 | ??6.4 | ??5.5 | ??5.4 | ??5.2 | ??5.1 |
| Peak number | ??10 | ??11 | ??12 | ??13 | ??14 | ??15 | ??16 | ??17 | |
| ??2_θ_(°) ??Cu | ??19.7 | ??22.9 | ??23.6 | ??24.9 | ??25.4 | ??25.9 | ??27.7 | ??29.5 | |
| The d distance | ??4.5 | ??3.9 | ??3.8 | ??3.6 | ???3.5 | ??3.4 | ???3.2 | ???3.0 |
| Peak number | ??1 | ??2 | ??3 | ??4 | ??5 | ??6 | ??7 | ??8 |
| ??2_θ_(°)Cu | ??8.4 | ??9.5 | ??10.2 | ??14.7 | ??16.8 | ??17.9 | ??22.6 | ??26.1 |
| The d distance | ??10.6 | ??9.3 | ??8.7 | ??6.0 | ??5.3 | ??5.0 | ??3.9 | ??3.4 |
| Peak number | ??1 | ???2 | ??3 | ???4 | ????5 | ???6 | ???7 | ???8 | ??9 |
| ??2_θ_(°) ??Cu | ???6.6 | ???8.6 | ??12.7 | ???13.3 | ????15.9 | ???18.6 | ???19.2 | ???20.1 | ??21.0 |
| The d distance | ???13.3 | ???10.3 | ??7.0 | ???6.6 | ????5.5 | ???4.8 | ???4.6 | ???4.4 | ??4.2 |
| Peak number | ???10 | ???11 | ??12 | ???13 | ????14 | ???15 | ???16 | ???17 | |
| ??2_θ_(°) ??Cu | ???22.5 | ???22.9 | ??23.6 | ???24.9 | ????25.4 | ????25.9 | ???27.7 | ???29.5 | |
| The d distance | ???4.0 | ???3.9 | ??3.8 | ???3.6 | ????3.5 | ?????3.4 | ???3.2 | ???3.0 |
Second embodiment of the present invention relates to the zwitterionic method of the trovafloxacin of preparation formula I, and it is selected from the polymorph PI of non-removing dampness as described above, and the polymorph PII and the pentahydrate thereof of removing dampness comprise:
The step of the waterborne suspension of the meta form of A processing formula I chemical compound:
1) use non-polar solven, azeotropic is removed remaining water and vacuum drying forms the polymorph PII that shows as the described removing dampness of the characteristic X-ray diffraction pattern of record in the claim 1 then;
2) use polar solvent, azeotropic is removed remaining water and vacuum drying then; Or
3) water and air drying residue at elevated temperatures, remove mother solution and the air at room temperature dried residue to constant weight to form pentahydrate; Or
B) the second polymorph PII that handles removing dampness with the polar solvent that refluxes forms the first polymorph PI of non-removing dampness.
The 3rd embodiment of the present invention provides the method for zwitterionic meta form of the trovafloxacin of preparation formula I, this be by
A) use the ackd salt of alkali treatment trovafloxacin at elevated temperatures, the pH of mixture brought up between 7.5 and 8.5, remove mother solution, water clean crystal and about 35 ℃ to about 40 ℃ of following vacuum drying crystal; Or
B) chemical compound of processing formula II
Wherein A is that H or amine protecting group are rolled into a ball as uncle-butoxy carbonyl, benzyloxycarbonyl, (C
1-C
6) alkyl-carbonyl and benzyl; With
B is H or is selected from benzyl, tert-butyl and (C
1-C
6) carboxylic acid protective group of alkyl; Remove protective agent with amine and/or carboxylic acid respectively.
The 4th embodiment of the present invention provides the method for treatment mammal bacterial infection, and it comprises the chemical compound to the I of formula as described above of described mammal administration bacterial infection treatment effective dose.
The 5th embodiment of the present invention provides the compositions of treatment mammal bacterial infection, and it comprises the formula I chemical compound and the pharmaceutically acceptable carrier of bacterial infection treatment effective dose.
The present invention relates to a kind of chemical compound, it comprises the stable zwitterionic form of the antibiotic trovafloxacin of formula I:
More particularly, it relates to the chemical compound of formula I, is selected from:
A) show as the non-removing dampness first polymorph PI of characteristic X-ray powder diffraction pattern as described above;
B) show as the removing dampness second polymorph PII of characteristic X-ray powder diffraction pattern as described above;
And c) pentahydrate shows as the trovafloxacin amphion pentahydrate of characteristic X-ray powder diffraction pattern as described above.
The present invention also relates to the chemical compound of preparation formula I, shown in following flow chart.
Flow chart 1
Flow chart 2
Zwitterionic meta form
Trovafloxacin salt I as shown in flow chart 1, wherein, X is an anion, it is selected from those by mineral acid example hydrochloric acid, sulphuric acid, nitric acid and phosphoric acid; Organic acid such as sulfonic acid, for example, benzenesulfonic acid (besylic), p-methyl benzenesulfonic acid (PTSA, tosylic), methanesulfonic acid (MSA, methylic) and trifluoromethanesulfonic acid (triflic) or the like; And carboxylic acid, the formed anion of acetic acid, propanoic acid, benzoic acid, citric acid, tartaric acid, maleic acid, fumaric acid, succinic acid and malic acid for example, by arriving about 55 ℃ temperature range about 45, the use aqueous slkali is brought up to the pH of the serosity of inclusion compound 1 between about 7.5 and 8.5, and changes metastable zwitterionic form 2 into.Preferred salt is mesylate.Be used for the alkali that the present invention puts into practice in this respect and comprise inorganic base such as alkali or alkaline earth hydroxide, carbonate and bicarbonate and organic base are as three (C
1-C
6) alkylamine, pyridine and morpholine.Preferred aqueous alkali is a saturated sodium bicarbonate.Under about 35 to 40 ℃ temperature, will wet the product vacuum drying then to constant weight.
In addition, as shown in flow chart 2, can directly prepare chemical compound 2 from the protected precursor 6 of the trovafloxacin salt 1 of formula II:
Wherein A is H or as uncle-butoxy carbonyl, benzyloxycarbonyl, (C
1-C
6) the amine protecting group group of alkyl-carbonyl and benzyl; With
B is H or is selected from benzyl, tert-butyl and (C
1-C
6) carboxylic acid protective group of alkyl; Respectively with amine and/or carboxylic acid for removing protective agent.
At elevated temperatures, with the preferred chemical compound 6 of naoh treatment, wherein A is that H and B are ethyls, and it is converted into chemical compound 2 in polar solvent, and preferred solvent is that methanol and temperature are the reflux temperatures of solvent.With dilute hydrochloric acid pH value of solution is transferred to about 6.5 and 8.0 then, and adds saturated aqueous NaHCO then
3PH is transferred between about 7.5 and 8.5, reclaims product specified as above.
Handle with non-polar solven such as hydrocarbon, metastable trovafloxacin amphion 2 is converted into the polymorph PII of removing dampness, 4, preferred hydrocarbon is a hexane.Azeotropic is removed residual water and is listed as about 40 ℃ of vacuum drying products at about 35 ℃.Be used for removing the solvent that anhydrates by azeotropic and comprise nonpolar fatty hydrocarbon, as hexane and octane and aromatic hydrocarbon such as benzene and toluene, preferred solvent is an aliphatic hydrocarbon, most preferably is hexane.
Handle chemical compound 2 with polar solvent, azeotropic removal of water and can prepare the polymorph PI3 of non-removing dampness to about 40 ℃ of vacuum dryings then at about 30 ℃, the polar solvent that is used for this conversion comprises (C
2-C
6) alkyl carboxylic acid (C
1-C
6) Arrcostab and (C
1-C
6) alkanol or the like, preferred solvent is an ethyl acetate.
In addition as mentioned above, handle chemical compound 4 with the backflow polar solvent, can prepare chemical compound 3, preferred solvent is an ethyl acetate.
At room temperature, the wet crystal of air drying chemical compound 1 is up to reaching constant weight, the pentahydrate of the chemical compound of preparation formula I, chemical compound 5.In addition, can prepare chemical compound 5 with water treatment chemical compound 4 up to reaching constant moisture absorption.Chemical compound 3 is exposed in the water can be converted into chemical compound 5.
Antibacterium compound of the present invention, i.e. polymorph PI, polymorph PII and pentahydrate (referring to " reactive compound " later on) can be used for treating the animal and human of broad-spectrum bacterial infection, and they are used in particular for treating gram-positive bacteria.
This reactive compound can be individually dosed, but usually put into practice the pharmaceutical carrier of selecting and form mixture and administration with the administration of planned route of administration and standard, for example, they can be oral or with the tablet form of the excipient that contains starch or lactose, or form admixture in capsule separately or with excipient, or with the elixir that contains flavour enhancer or coloring agent or the form administration of suspension.For animal, they can advantageously be included in animal foodstuff or the drinking-water, concentration about 5 to about 5000ppm, preferred about 25 to about 500ppm.Their can parenteral ground inject, for example intramuscular, intravenous or subcutaneous injection, for the parenteral administration, they preferably can contain other solute, for example enough salt or glucose are so that the form of the isoosmotic sterilization aqueous solution of solution and using.For animal, the chemical compound of formula I can intramuscular or subcutaneous administration, and dosage level about 0.1 was by about 50mg/kg/ days, and advantageously about 0.2 is listed as about 10mg/kg/ days, if take medicine once a day or to being divided into three administrations.
But through port is taken or the parenteral route is applied to the people with the treatment bacterial disease with reactive compound of the present invention, oral administration dosage level about 0.1 was by 500mg/kg/ days, advantageously about 0.5 by 50mg/kg/ days, in dosage once a day or to the divided dose that is divided into three times.For intramuscular or intravenous administration, the about 0.1-200mg/kg/ of dosage level days, advantageously 0.5-50mg/kg/ days, the muscle administration can be dose or arrive and divide three dosage that intravenous administration can comprise continuous drip.According to being done a little variations by the body weight of treatment target and situation and selected special route of administration, this is that those those of ordinary skill in the art will be appreciated that.
With the antibacterial activity that provides The compounds of this invention according to Steers replicator technical testing, this technology is the testing in vitro method of standard, and this is at E.Steers etc., antibiotic and chemotherapy, 9,307, record in (1959).
Following embodiment shows method of the present invention and chemical compound.But, should be appreciated that the present invention is not limited to these certain embodiments.
Embodiment 1
The trovafloxacin amphion, the meta form
A. trovafloxacin mesylate (according to the embodiment 13B preparation of ' 402 patents) (20 gram) stirs with deionized water (100 milliliters).With this crystal serosity be heated to about 50 ℃ and add saturated sodium bicarbonate solution slurry pH is transferred to about 8.0, this slurry be maintained at about 50 ℃ 30 minutes, be cooled to about 25 ℃ and stirred 30 minutes in this temperature.Filter to isolate crystal and use deionized water (27ml) to clean.The crystal that will wet is suspended in deionized water (100 milliliters) and about 50 ℃ of stir abouts 1 hour; From mother solution, filter out crystal, with deionized water (about 27 milliliters) clean and at about 40 ℃ of vacuum dryings to constant weight, produce title product, contain 2.5% residual water by analyzing it, product 16.25 grams, 97%.
B. the ethyl ester of trovafloxacin is (according to the U.S. Patent application 08/490827 of common pending trial, submit to June 15 nineteen ninety-five the method preparation, its content is introduced the present invention as a reference and fully, above-mentioned patent and the application transfer the possession of together) (10 gram) and methanol (75 milliliters), water (25 milliliters) and sodium hydroxide sheet (1.8 gram) stir together.The about 72 ℃ of reflux of reactant mixture to form solution, are cooled off this solution to about 25 ℃ and regulate pH to about 7.5 to form slurry by adding 6N hydrochloric acid, add saturated sodium bicarbonate solution (50 milliliters) and slurry was stirred 30 minutes at about 25 ℃.Isolate title product and water (20 milliliters) cleaning and, produce product 7.72 grams, 82.5% at about 45 ℃ of vacuum dryings.
Embodiment 2
Trovafloxacin amphion polymorph PI (non-removing dampness form)
Trovafloxacin methanesulfonates (75 gram) stirs with deionized water (375 milliliters), the crystal slurry is heated to about 50 ℃ and by adding saturated sodium bicarbonate solution the pH of slurry is transferred to about 8.0, the temperature that keeps slurry about 50 ℃ 30 minutes, be cooled to about 25 ℃ and stirred 30 minutes in this temperature.Filter to isolate crystal and clean with deionized water (100 milliliters), the crystal that will wet is suspended in the deionized water (375 milliliters) and at about 50 ℃ and stirred 1 hour, is cooled to about 20 ℃ and this relaxing the bowels with purgatives of warm nature stir about 1 hour then.From mother solution, filter out crystallized product and use deionized water (about 100 milliliters) to clean, and the wet crystal of ethyl acetate (1125 milliliters) stirring, and with gained slurry reflux and azeotropic removal of water.This anhydrous basically slurry is cooled to about 25 ℃, filter to isolate crystal and at about 40 ℃ of vacuum dryings up to removing all solvents obtaining title product, product 60.9 grams, 94%.
Can characterize this product by X-powder diffraction pattern described above.
Embodiment 3
The polymorph PII of trovafloxacin amphion removing dampness
Embodiment 1, and the title compound of A part (5 gram) mixes the formation slurry with hexane (150 milliliters).Slurry reflux and azeotropic are removed the residual water of trace, and refluxing was cooled to about 25 ℃ with the crystal slurry after 4 hours, isolated by filtration and at about 40 ℃ of vacuum dryings to constant weight.Product 4.7 grams, 94%.Characterize this title product by X-powder diffraction pattern described above.
Embodiment 4
Trovafloxacin amphion pentahydrate
Trovafloxacin methanesulfonates (50 gram) stirs with deionized water (250 milliliters), the crystal slurry is heated to 50 ℃ and by adding saturated sodium bicarbonate solution the pH of slurry is transferred to about 8.0, slurry was kept 30 minutes about 25 ℃ and stirred 30 minutes of cooling row in this temperature at about 50 ℃.Isolated by filtration goes out this crystal and cleans with deionized water (70 milliliters), and the crystal that will wet is suspended in deionized water (250 milliliters) and stirred 1 hour at about 50 ℃, is cooled to about 20 ℃ and this temperature stir about 1 hour then.Filter out crystallized product from mother solution, clean with deionized water (about 70 milliliters), at room temperature this wet crystal of air drying produces title product to constant weight, contains 17.6% water by analyzing it.Product 48.4 grams, 84%.
Characterize this title product by X-powder diffraction pattern described above.
Claims (20)
1. the trovafloxacin amphion crystal form of a formula I:
Be selected from;
A) show as the non-removing dampness first polymorph PI of following characteristic X-ray powder diffraction pattern
Peak number ??1 ??2 ??3 ??4 ??5 ??6 ??7 ??8 ??9
??2_θ_(°)Cu ??6.9 ??9.8 ??11.3 ??12.0 ??13.9 ??16.1 ??16.6 ??17.1 ??17.4
The d distance ??12.7 ??9.0 ??7.9 ??7.4 ??6.4 ??5.5 ??5.4 ??5.2 ??5.1
Peak number ??10 ??11 ??12 ??13 ??14 ??15
??2_θ_(°)Cu ??19.7 ??20.3 ??21.2 ??22.8 ??23.8 ??26.3
The d distance ??4.5 ??4.4 ??4.2 ??3.9 ??3.7 ??3.4
B) show as the removing dampness second polymorph PII of following characteristic X-ray powder diffraction pattern
Peak number ??1 ??2 ??3 ??4 ?5 ??6 ??7 ??8
??2_θ_(°)Cu ??8.4 ??9.5 ??10.2 ??14.7 ?16.8 ??17.9 ??22.6 ??26.1
The d distance ??10.6 ??9.3 ??8.7 ??6.0 ?5.3 ??5.0 ??3.9 ??3.4
And c) pentahydrate shows as the trovafloxacin amphion pentahydrate of following characteristic X-ray powder diffraction pattern.
Peak number ??1 ??2 ??3 ??4 ??5 ??6 ??7 ??8 ??9
??2_θ_(°) ??Cu ??6.6 ??8.6 ??12.7 ??13.3 ??15.9 ??18.6 ??19.2 ??20.1 ??21.0
The d distance ??13.3 ??10.3 ??7.0 ??6.6 ??5.5 ??4.8 ??4.6 ??4.4 ??4.2
Peak number ??10 ??11 ??12 ??13 ??14 ??15 ??16 ??17
??2_θ_(°) ??Cu ??22.6 ??22.9 ??23.6 ??24.9 ??25.4 ??25.9 ??27.7 ??29.5
The d distance ??3.9 ??3.8 ??3.6 ??3.5 ??3.4 ??3.2 ??3.0
2. the chemical compound of claim 1 comprises the first polymorph PI of described non-removing dampness.
3. the chemical compound of claim 1 comprises the second polymorph PII of described removing dampness.
4. the chemical compound of claim 1 comprises described pentahydrate.
5. the chemical compound of claim 1 comprises described meta form.
6. the method for a preparation I compound,
It is selected from the polymorph PI of non-removing dampness, and the polymorph PII of removing dampness and its pentahydrate comprise:
The step of the waterborne suspension of the meta form of A, processing formula I chemical compound:
1) use non-polar solven, azeotropic is removed remaining water and vacuum drying forms the polymorph PII that shows as the described removing dampness of the characteristic X-ray diffraction pattern of record in the claim 1 then;
2) use polar solvent, azeotropic is removed remaining water and vacuum drying then; Or
3) water and air drying residue at elevated temperatures, remove mother solution and the air at room temperature dried residue to constant weight to form pentahydrate; Or
B) the second polymorph PII that handles removing dampness with the polar solvent that refluxes forms the first polymorph PI of non-removing dampness.
7. the method for claim 6, the meta form of the chemical compound of its Chinese style I, by being prepared as follows:
A) at elevated temperatures, with the hydrochlorate of alkali treatment trovafloxacin, the pH of mixture is brought up between 7.5 and 8.5; Or
B) pass through, respectively with amine and/or carboxylic acid for removing protective agent, handle the chemical compound of formula II
Wherein A is H or amine protecting group group, as uncle-butoxy carbonyl, benzyloxycarbonyl, (C
1-C
6) alkyl-carbonyl and benzyl; And B is H or is selected from benzyl, tert-butyl and (C
1-C
6) carboxylic acid protective group of alkyl.
8. the method in claim 6 step a), non-polar solven wherein is a hexane.
9. the method in claim 6 step b), polar solvent wherein is an ethyl acetate.
10. a method for the treatment of the mammal bacterial infection comprises the chemical compound to the claim 1 of described administration bacterial infection treatment effective dose.
11. the method for claim 10, wherein said chemical compound are the first polymorph PI of non-removing dampness.
12. the method for claim 10 comprises that said chemical compound is the second polymorph PII of removing dampness.
13. the method for claim 10, wherein said chemical compound are trovafloxacin amphion pentahydrates.
14. a compositions that is used for the treatment of the mammal bacterial infection comprises chemical compound and pharmaceutically acceptable carrier that bacterial infection is treated the claim 1 of effective dose.
15. the compositions of claim 14, wherein said chemical compound are the first polymorph PI of non-removing dampness.
16. the compositions of claim 14, wherein said chemical compound are the second polymorph PII of removing dampness.
17. the compositions of claim 14, wherein said chemical compound are trovafloxacin amphion pentahydrates.
18. the chemical compound of claim 14, wherein said compositions are a kind of suspensions.
19. the method for claim 7, wherein A is H or amine protecting group group, as uncle-butoxy carbonyl, benzyloxycarbonyl, (C
1-C
6) alkyl-carbonyl and benzyl.
20. the method for claim 7, wherein said chemical compound are B is that H and A are selected from benzyl, tert-butyl and (C
1-C
6) alkyl.
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)
| Publication Number | Publication Date |
|---|---|
| CN1190889A true CN1190889A (en) | 1998-08-19 |
Family
ID=21703460
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96195624A Pending CN1190889A (en) | 1995-08-29 | 1996-07-29 | Zwitterionic forms of trovafloxacin |
Country Status (30)
| Country | Link |
|---|---|
| EP (1) | EP0850060A1 (en) |
| JP (1) | JP3188476B2 (en) |
| KR (1) | KR100343909B1 (en) |
| CN (1) | CN1190889A (en) |
| AP (1) | AP636A (en) |
| AR (1) | AR003985A1 (en) |
| AU (1) | AU704115B2 (en) |
| BR (1) | BR9609998A (en) |
| CA (1) | CA2229786C (en) |
| CO (1) | CO4480739A1 (en) |
| CZ (1) | CZ56698A3 (en) |
| DZ (1) | DZ2087A1 (en) |
| GT (1) | GT199600072A (en) |
| HR (1) | HRP960395B1 (en) |
| HU (1) | HUP9900170A3 (en) |
| IL (1) | IL122651A (en) |
| MA (1) | MA23966A1 (en) |
| MY (1) | MY113874A (en) |
| NO (1) | NO309814B1 (en) |
| NZ (1) | NZ312199A (en) |
| OA (1) | OA10669A (en) |
| PE (1) | PE12598A1 (en) |
| PL (1) | PL325170A1 (en) |
| RU (1) | RU2144921C1 (en) |
| SK (1) | SK23898A3 (en) |
| TN (1) | TNSN96109A1 (en) |
| TR (1) | TR199800339T1 (en) |
| WO (1) | WO1997007800A1 (en) |
| YU (1) | YU48396A (en) |
| ZA (1) | ZA967282B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HN1998000106A (en) | 1997-08-01 | 1999-01-08 | Pfizer Prod Inc | PARENTERAL COMPOSITIONS OF ALATROFLAXACINO |
| US7019142B2 (en) | 1998-01-16 | 2006-03-28 | Pfizer Inc. | Process for preparing naphthyridones and intermediates |
| PA8466701A1 (en) * | 1998-01-21 | 2000-09-29 | Pfizer Prod Inc | TROVAFLOXACINO MESYLATE TABLET |
| US6114531A (en) * | 1998-07-28 | 2000-09-05 | Pfizer Inc. | Process for preparing quinolone and naphthyridone carboxylic acids |
| HN1999000141A (en) * | 1998-09-03 | 2000-06-19 | Pfizer Prod Inc | PROCEDURE FOR PREPARING SALTS OF TROVAFLOXACIN FOR ADDITION OF ACIDS. |
| US6239141B1 (en) | 1999-06-04 | 2001-05-29 | Pfizer Inc. | Trovafloxacin oral suspensions |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5164402A (en) * | 1989-08-16 | 1992-11-17 | Pfizer Inc | Azabicyclo quinolone and naphthyridinone carboxylic acids |
-
1996
- 1996-07-29 CN CN96195624A patent/CN1190889A/en active Pending
- 1996-07-29 KR KR10-1998-0701468A patent/KR100343909B1/en not_active IP Right Cessation
- 1996-07-29 PL PL96325170A patent/PL325170A1/en unknown
- 1996-07-29 EP EP96923020A patent/EP0850060A1/en not_active Withdrawn
- 1996-07-29 SK SK238-98A patent/SK23898A3/en unknown
- 1996-07-29 HU HU9900170A patent/HUP9900170A3/en unknown
- 1996-07-29 CA CA002229786A patent/CA2229786C/en not_active Expired - Fee Related
- 1996-07-29 TR TR1998/00339T patent/TR199800339T1/en unknown
- 1996-07-29 RU RU98103873/04A patent/RU2144921C1/en not_active IP Right Cessation
- 1996-07-29 WO PCT/IB1996/000756 patent/WO1997007800A1/en not_active Application Discontinuation
- 1996-07-29 NZ NZ312199A patent/NZ312199A/en unknown
- 1996-07-29 BR BR9609998A patent/BR9609998A/en unknown
- 1996-07-29 AU AU63676/96A patent/AU704115B2/en not_active Ceased
- 1996-07-29 IL IL12265196A patent/IL122651A/en not_active IP Right Cessation
- 1996-07-29 JP JP50343697A patent/JP3188476B2/en not_active Expired - Fee Related
- 1996-07-29 CZ CZ98566A patent/CZ56698A3/en unknown
- 1996-08-23 GT GT199600072A patent/GT199600072A/en unknown
- 1996-08-26 AR ARP960104121A patent/AR003985A1/en unknown
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- 1996-08-28 DZ DZ960131A patent/DZ2087A1/en active
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- 1996-08-28 MY MYPI96003579A patent/MY113874A/en unknown
- 1996-08-29 CO CO96046149A patent/CO4480739A1/en unknown
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1998
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