AP788A - Novel crystal form of anhydrous 7-(1a, 5a, 6a)-6-Amino-3-Azabicyclo(3.1.0) hex-3-YI)-6-Fluoro-1-(2,4- Difluorophenyl)-1,4-Dihydro-4-Oxo-1, 8-Naphthyridine-3-Carboxylic Acid, Methanesulfonic acid salt. - Google Patents
Novel crystal form of anhydrous 7-(1a, 5a, 6a)-6-Amino-3-Azabicyclo(3.1.0) hex-3-YI)-6-Fluoro-1-(2,4- Difluorophenyl)-1,4-Dihydro-4-Oxo-1, 8-Naphthyridine-3-Carboxylic Acid, Methanesulfonic acid salt. Download PDFInfo
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- AP788A AP788A APAP/P/1996/000851A AP9600851A AP788A AP 788 A AP788 A AP 788A AP 9600851 A AP9600851 A AP 9600851A AP 788 A AP788 A AP 788A
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- oxo
- dihydro
- fluoro
- amino
- naphthyridine
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- 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
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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
- A61K31/4353—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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Abstract
Theanhydrateof7-([1a,5a,6a]-6-amino-3-azabicyGlo[3.1.0]hex-3-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonic acid salt has advantageous stability for formulation as an antibacterial agent.
Description
NOVEL CRYSTAL FORM OF ANHYDROUS 7-([1σ,5σ,6σ1-6-ΑΜΙΝΟ-3AZABICYCLOf3.1.01HEX-3-YL)-6-FLUORO-1-(2.4-DIFLUOROPHENYL)-1,4DIHYDRO-4-OXO-1.8-NAPHTHYRIDINE-3-CARBQXYLIC ACID,
METHANESULFONIC ACID SALT
Background of the Invention
The invention is directed to a novel crystal form of anhydrous 7-([1σ,5σ,6σ]-6amino-3-azabicyclo[3.1,0]hex-3-yl)-6-fluoro-1 -(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8naphthyridine-3-carboxylic acid, methanesulfonic acid salt, a method of using said compound in the treatment of a bacterial infection in mammals, especially humans, and to pharmaceutical compositions useful therefor.
United States Patent No. 5,229,396, which is incorporated herein by reference, discloses 7-([1a,5a,6a]-6-amino-3-azabicycio[3.1,0jhex-3-yl)-6-fluoro-1 -(2,4difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,methanesulfonic acid salt of the formula
CH3SO3H wherein Y is o,p-difluorophenyl and R2 is
AP/P/ 9 6 / 0 0 851
having antibacterial activity.
AP . ϋ υ 7 8 8
-2Summary of the Invention
The invention is directed to a novel crystal form of anhydrous 7-([1σ,5σ,6σ]-6amino-3-azabicyclo[3.1,0]hex-3-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8naphthyridine-3-carboxylic acid, methanesulfonic acid salt which possesses valuable and nonobvious properties. Since the anhydrate is substantially hydrophobically stable, formulation problems of the active ingredient during tableting or capsulation operations are alleviated.
Detailed Description of the Invention
The 7-([1a,5a,6a]-6-amino-3-azabicyclo[3.1.0]hex-3-yl)-6-fluoro-1-(2,410 difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,methanesulfonic acid salt referred to in United States Patent No. 5,229,396 characterized by the major peaks in the following X-ray powder diffraction pattern
| Peak no. | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 |
| 20(°) Cu | 5.0 | 9.8 | 13.0 | 14.8 | 19.7 | 20.9 | 22.0 | 23.0 | 28.1 | 29.3 |
| d space | 17.9 | 9.0 | 6.8 | 6.0 | 4.5 | 4.2 | 4.0 | 3.9 | 3.2 | 3.0 |
is substantially hygroscopic and can pick up water from the atmosphere to form a monohydrate. The monohydrate is characterized by the major peaks in the following
X-ray powder diffraction pattern
15800 / 96 /'d/dV
| Peak no. | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
| 20(°) Cu | 4.7 | 9.4 | 12.4 | 13.1 | 13.6 | 14.2 | 17.0 | 17.9 |
| d space | 8.7 | 9.4 | 7.1 | 6.7 | 6.5 | 6.3 | 5.2 | 5.0 |
| Peak no. | 9 | 10 | 11 | 12 | 12 | 14 | 15 | |
| 20(°) Cu | 8.7 | 21.0 | 22.0 | 24.2 | 24.2 | 26.6 | 27.2 | |
| d space | 4.7 | 4.2 | 4.0 | 3.7 | 3.7 | 3.5 | 3.3 |
The novel crystal form of 7-([1a,5a,6a]-6-amino-3-azabicyclo[3.1.0]hex-3-yl)-6fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonic acid salt (hereinafter the anhydrate) is hydrophobically stable and characterized by the major peaks in the following X-ray powder diffraction pattern.
AP . ύ υ 7 8 8
| Peak no. | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
| 20(°) Cu | 4.5 | 7.7 | 9.1 | 13.6 | 15.0 | 18.2 | 18.6 | 22.8 |
| d space | 19.5 | 11.5 | 9.7 | 6.5 | 5.9 | 4.9 | 4.8 | 3.9 |
The anhydrate may be prepared by heating 7-([1a,5a,6o]-6-amino-3azabicyclo[3.1,0]hex-3-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8naphthyridine-3-carboxylic acid, methanesulfonic acid salt or its derived monohydrate in an organic solvent or a mixture thereof with an aprotic co-solvent, such as isopropanol, dimethylsulfoxide, n-propanol, tetrahydrofuran or n-butanol, preferably n-butanol or tetrahydrofuran/n-butanol, to reflux or to a temperature between about 70°C to about 90°C, preferably about 85°C. Depending on the reaction temperature and other conditions, the reaction time generally ranges from about 1 hour to about 20 hours, preferably about 2 hours to about 16 hours.
The crystal slurry formed is cooled to a temperature between about 20°C to about 30°C, preferably about 25°C, for a time period between about 2 hours to about 24 hours, preferably about 2 hours to about 12 hours. The crystalline product is then filtered from the mother liquid and dried under vacuum until all the solvent has been removed.
The anhydrate may be administered as an antibacterial agent as described in above-mentioned United States Patent No. 5,229,396. Administration to a subject may be alone, but the anhydrate will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, it 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, it is advantageously contained in an animal feed.
The invention also provides pharmaceutical compositions comprising an antibacteriaily effective amount of the anhydrate together with a pharmaceutically acceptable diluent or carrier.
The anhydrate can be administered to humans for the treatment of bacterial diseases by either the 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
AP/P/ 9 6 / 0 0 8 5 1
AP.00788 in a single dose or up to 3 divided doses. 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 antibacterial activity of the anhydrate 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 hydration properties were determined gravimetrically over a range of relative humidities using a VTI microbalance system for moisture sorption studies (Model MB300W).
PREPARATION A
7-(H g,5g,6flfl-6-amino-3-azabicvclor3.1.01hex-3-yl)-6-fluoro-1 (2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxy lie acid, methanesulfonic acid salt
7-([1σ, 5σ, 6a]-6-tert-butyloxycarbonylamino-3-azabicyclo]3,1.0]hex-3yl)-6-fluoro1 (2,4-difIuorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.ethylester, (25 g) and methanesulfonic acid (11 g) was added to a mixture of water (250 mL) and tetrahydroiuran (250 mL). The resultant slurry was heated to reflux (about 66°C) temperature and held at this temperature for 20 hours after which time a clear solution was obtained. The solution was cooled to 35-40°C and concentrated under reduced pressure to about half its original volume. The resultant crystal slurry was cooled slowly to room temperature (about 20°C) and then further stirred at 10°C for 2 hours. The crystalline product 7-([1ff,5a,6a]-6-amino-3-azabicyclo[3.1.3]hex-3-yl)-6-fluoro-1(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonic acid salt was isolated by filtration and washed with a mixture of tetrahydroiuran (12.5 mL) and water (12.5 mL). The crystals were dried under vacuum at 30-35° until the residual water content of the crystals was below 0.2%. Yield 21.2 g, 90%.
The crystals of 7-([1a,5a,6a]-6-amino-3-azabicyclo[3.1.0]hex-3-yl)-6-fluoroAP/P/ 9 6 / 0 0 8 5 1
AP . Ο Ο 7 8 8
1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonic acid salt are characterized by the major peaks in the following X-ray powder diffraction pattern.
| Peak no. | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 |
| 20(°) Cu | 5.0 | 9.8 | 13.0 | 14.8 | 19.7 | 20.9 | 22.0 | 23.0 | 28.1 | 29.3 |
| d space | 17.9 | 9.0 | 6.8 | 6.0 | 4.5 | 4.2 | 4.0 | 3.9 | 3.2 | 3.0 |
The crystals of 7-([1a,5a,6a]-6-amino-3-azabicyclo[3.1,0]hex-3-yl)-6-fluoro10 1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxyiic acid, methanesulfonic acid salt can pick up water from the atmosphere and form a monohydrate. The monohydrate is characterized by the major peaks in the following X-ray powder diffraction pattern.
| Peak no. | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
| 20(°) Cu | 4.7 | 9.4 | 12.4 | 13.1 | 13.6 | 14.2 | 17.0 | 17.9 |
| d space | 8.7 | 9.4 | 7.1 | 6.7 | 6.5 | 6.3 | 5.2 | 5.0 |
| Peak no. | 9 | 10 | 11 | 12 | 12 | 14 | 15 | |
| 20(°) Cu | 8.7 | 21.0 | 22.0 | 24.2 | 24.2 | 26.6 | 27.2 | |
| d space | 4.7 | 4.2 | 4.0 | 3.7 | 3.7 | 3.5 | 3.3 |
AP/P/ 9 6 / 0 0 8 5 1 ~
Example 1
7-(f1g, 5a, 6q1-6-amino-3-azabicycloF3.1.0Thex-3v)-6-fluoro-1-(2,4difluorophenvl)-1.4-dihvdro-4-oxo-118-naphthvridine-3-carboxvlic acid, methanesulfonic acid salt, anhydrous
7-([1 a,5a,6a]-6-amino-3-azabicyclo[3.1.0]hex-3-yl)-6-fluoro-1 -(2,4difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,methanesulfonic acid salt or its monohydrate (20 g) was stirred with isopropanol (220 ml). The crystal suspension was refluxed for 16 hours or until microscopic examination had shown that the crystal form had changed to a hexagonal form. The crystal slurry was cooled to 2030 25°C and stirred at this temperature for about 1 hour. The crystalline product was filtered from the mother liquor, washed with isopropanol (about 50 mL) and dried under vacuum at 40°C until all the solvent had been removed. Yield 98%.
AP . ι> Ο 7 β 8
-6The product is a new polymorphic form of 7-([1a,5a,6a]-6-amino-3azabicyclo[3.1.0]hex-3-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8naphthyridine-3-carboxylic acid, methanesulfonic acid salt, anhydrous, characterized by the following major peaks in its X-ray powder diffraction pattern.
| Peak no. | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
| 20(°) Cu | 4.5 | 7.7 | 9.1 | 13.6 | 15.0 | 18.2 | 18.6 | 22.8 |
| d space | 9.5 | 11.5 | 9.7 | 6.5 | 5.9 | 4.9 | 4.8 | 3.9 |
Example 2
7-(Γ1σ, 5σ, 6ql-6-amino-3-azabicvclor3.1.0lhex-3y)-6-fluoro-1-(2,4difluorophenvi)-1,4-dihydro-4-oxo-1.8-naphthvridine-3-carboxyjic acid, methanesulfonic acid salt, anhydrous
7-((1 a,5a,6a]-6-am ino-3-azabicyclo [3.1,0]hex-3-yl)-6-fluoro-1 -(2,4difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,methanesulfonic acid salt or its monohydrate (7 g) was dissolved in dimethylsulfoxide, DMSO (21 mL) by heating to 80-85°C until complete solution was obtained. Isopropanol (150 mL) was added dropwise to the solution at about 85°C to induce crystallization. The crystal ' suspension was held at reflux temperature about 85°C for 2-16 hours or until microscopic examination had shown that the crystal form had changed to a hexagonal form. The resultant crystal slurry was cooled to 20-25°C. The crystalline product was filtered from the mother liquor, washed with isopropanol (about 50 mL) and dried under vacuum at 50°C until all the solvents had been removed. Yield 77%.
The product is the same as in Example 1.
Example 3
7-(Γ1σ, 5σ, 6a1-6-amino-3-azabicycloi3.1.01hex-3y)-6-fluoro-1-(2,4difluoropheny 1)-1,4-dihvdro-4-oxo-1,8-naphthyridine-3-carboxy lie acid, methanesulfonic acid salt, anhydrous
7-([1q,5a,6a]-6-amino-3-azabicyclo[3.1.0]hex-3-yl)-6-fluoro-1 -(2,4difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,methanesulfonic acid salt or its monohydrate (55.6 g) was dissolved in dimethylsulfoxide, DMSO (159 mL) by heating to 80-85°C until complete solution was obtained. The solution was cooled to 20-25°C and stirred for 2 hours until a crystal slurry formed.
8 0 0 / 9 6 /d/dV
AP . Ο Ο 7 8 8
-7ζ Dichioromethane (1200 mL) was added dropwise to the solution at about 25°C to fully induce crystallization. The crystal suspension was held at room temperature overnight or until microscopic examination had shown that the crystal form had changed to a hexagonal form. The crystalline product was filtered from the mother liquor, washed with dichioromethane (3x119 mL) and dried under vacuum at 50°C until all the solvent had been removed. Yield 91%.
The product is the same as in Example 1.
Example 4
7-(Γ1σ, 5σ, 6gl-6-amino-3-azabicyclo(3.1.0Thex-3v)-6-fluoro-1-(2,410 difluorophenvl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonic acid salt anhydrous
7-((1 a,5g,6g]-6-amino-3-azabicyclo[3.1,0]hex-3-yl)-6-fluoro-1 -(2,4difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,methanesulfonic acid salt or its monohydrate (1 g) was stirred with n-propanol (44 mL). The crystal suspension was refluxed for 3 hours or until microscopic examination had shown that the crystal form had changed to a hexagonal form. The crystal slurry was cooled at 2025°C and stirred overnight. The crystalline product was filtered from the mother liquor, • washed with n-propanol (about 10 mL) and dried under vacuum at 50-55°C until all the solvent had been removed. Yield 68%.
The product is the same as in Example 1.
,- -., Example 5
7-((1 σ, 5a, 6gT-6-amino-3-azabicvclof3.1.01hex-3y)-6-fluoro-1-(2,4difluorophenvl)-1,4-dihydro-4-oxo-1,8-naphthvridine-3-carboxylic acid, methanesulfonic acid salt, anhydrous
7-([1g,5g,6a]-6-amino-3-azabicyclo[3.1 .Olhex-S-yO-e-fluoro-l-^^difluorophenyO-l ,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,methanesulfonic acid salt or its monohydrate (70 g) was stirred with a mixture of tetrahydrofuran (175 mL) and a n-butanol (525 mL). The crystal suspension was heated for 16 hours or until microscopic examination had shown that the crystal form had changed to a hexagonal form. The crystal slurry was cooled to 20-25°C and stirred overnight. The crystalline product was filtered from the mother liquor, washed with a mixture of tetrahydrofuran (25 mL) and n-butanol (75 mL) and dried under vacuum at 80°C until all the solvent had been removed. Yield 95%.
AP/P/ 9 6/00851
AP . ο ο 7 8 8
-8The product is the same as in Example 1.
Example 6
7-((1 σ, 5σ, 6g1-6-amino-3-azabicyclo(3.1.0Thex-3v)-6-fluoro-1-(2,4difluorophenyl)-1.4-dihvdro-4-oxo-1,8-naphthvridine-3-carboxylic acid, methanesulfonic acid salt, anhydrous
7-([1 g,5g,6a]-6-amino-3-azabicyclo[3.1,0]hex-3-yl)-6-fluoro-1 -(2,4difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,methanesulfonic acid salt or its monohydrate (5 g) was stirred with n-butanol containing up to 1% water (220 mL). The crystal suspension was heated to reflux for 5 hours or until microscopic 10 examination had shown that the crystal form had changed to a hexagonal form. The crystal slurry was cooled to 20-25°C and stirred overnight. The crystalline product was filtered from the mother liquor, washed with n-butanol (about 20 mL) and dried under vacuum at 50-55°C until all the solvent had been removed. Yield 92%.
The product is the same as in Example 1.
Claims (4)
1. 7-((1 o,5a,6a]-6-amino-3-azabicyclo[3.1,0]hex-3-yl)-6-fluoro-1-(
2,4difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,methanesulfonic acid salt characterized by the following major peaks in its X-ray powder diffraction
5 pattern
10 2. A pharmaceutical composition having antibacterial activity comprising the compound according to claim 1 in an amount effective in the treatment of a bacterial infection, and a pharmaceutically acceptable carrier.
3. A method of treating a bacterial infection which comprises administering to a subject in need of treatment an antibacterial amount of the compound according
15 to claim 1.
4. A process for preparing the compound according to claim 1, which comprises heating 7-((1 a,5o,6a]-6-amino-3-azabicyclo[3.1.0]hex-3-yl)-6-fluoro-1 -(2,4difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,methanesulfonic acid salt or its derived monohydrate in the presence of an alcohol or mixture thereof
20 with an aprotic co-solvent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| APAP/P/1996/000851A AP788A (en) | 1996-08-26 | 1996-08-26 | Novel crystal form of anhydrous 7-(1a, 5a, 6a)-6-Amino-3-Azabicyclo(3.1.0) hex-3-YI)-6-Fluoro-1-(2,4- Difluorophenyl)-1,4-Dihydro-4-Oxo-1, 8-Naphthyridine-3-Carboxylic Acid, Methanesulfonic acid salt. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| APAP/P/1996/000851A AP788A (en) | 1996-08-26 | 1996-08-26 | Novel crystal form of anhydrous 7-(1a, 5a, 6a)-6-Amino-3-Azabicyclo(3.1.0) hex-3-YI)-6-Fluoro-1-(2,4- Difluorophenyl)-1,4-Dihydro-4-Oxo-1, 8-Naphthyridine-3-Carboxylic Acid, Methanesulfonic acid salt. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AP9600851A0 AP9600851A0 (en) | 1996-10-31 |
| AP788A true AP788A (en) | 1999-12-03 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| APAP/P/1996/000851A AP788A (en) | 1996-08-26 | 1996-08-26 | Novel crystal form of anhydrous 7-(1a, 5a, 6a)-6-Amino-3-Azabicyclo(3.1.0) hex-3-YI)-6-Fluoro-1-(2,4- Difluorophenyl)-1,4-Dihydro-4-Oxo-1, 8-Naphthyridine-3-Carboxylic Acid, Methanesulfonic acid salt. |
Country Status (1)
| Country | Link |
|---|---|
| AP (1) | AP788A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0413455A2 (en) * | 1989-08-16 | 1991-02-20 | Pfizer Inc. | Azabicyclo quinolone carboxylic acids |
-
1996
- 1996-08-26 AP APAP/P/1996/000851A patent/AP788A/en active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0413455A2 (en) * | 1989-08-16 | 1991-02-20 | Pfizer Inc. | Azabicyclo quinolone carboxylic acids |
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| Publication number | Publication date |
|---|---|
| AP9600851A0 (en) | 1996-10-31 |
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