OA10293A - Novel crystal form of anhydrous 7-(Ä1alpha, 5alpha, 6alphaÜ-6-amino-3-azabicyclo Ä3.1.0Ü hex-3-yl)-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-(Ä1alpha, 5alpha, 6alphaÜ-6-amino-3-azabicyclo Ä3.1.0Ü hex-3-yl)-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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- OA10293A OA10293A OA60835A OA60835A OA10293A OA 10293 A OA10293 A OA 10293A OA 60835 A OA60835 A OA 60835A OA 60835 A OA60835 A OA 60835A OA 10293 A OA10293 A OA 10293A
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- naphthyridine
- difluorophenyl
- dihydro
- oxo
- fluoro
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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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Description
-ι- οί 0293 5 NOVEL CRYSTAL FORM OF ANHYDROUS 7-(Μα,5σ,6σ1-6-ΑΜΙΝΟ-3- AZABICYCLOf3.1 .OlHEX-3-YL)-6-FLUORO-1-(2.4-DIFLUOROPHENYL)-1 ,4- DIHYDRO-4-OXO-1.8-NAPHTHYRIDINE-3-CARBOXYLIC ACID,
METHANESULFONIC ACID SALT
Backqround of the Invention 10 The invention is directed to a novel crystal form of anhydrous 7-([1σ,5σ,6σ]-6- amino-3-azabicyclo[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 sait, a method of using saidcocnpound in the treatment of a bacterial infection in mammals, especially humans, andto pharmaceutical compositions useful therefor. 15 United States Patent No. 5,229,396, which is incorporated herein by référencé, discloses 7-([1a,5a,6a]-6-amino-3-azabicyclo[3.1.0]hex-3-yl)-6-fluoro-1-(2,4-difîiuorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,methanesulfonicadd sait of the formula 20 25
CH3SO3H wherein Y is o,p-difluorophenyl and R2 is 30 35
having antîbacterial activity. 010293 -2-
Summary of the Invention
The invention is directed to a novel crystal form of anhydrous 7-([1σ,5σ,6σ]-6-amino-3-azabicyclo[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 sait which possesses valuableand nonobvious properties. Sincethe anhydrate is substantially hydrophobically stable,formulation problème of the active ingrédient during tableting or capsulation operationsare alleviated.
Detailed Description of the Invention
The 7-([ 1 o,5a,6a]-6-amino-3-azabicyclo[3.1,0]hex-3-yl)-6-fluoro-1 -(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid .methanesulfonicacid sait referred to in United States Patent No. 5,229,396 characterized by the majorpeaks 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 atmosphère to form amonohydrate. The monohydrate is characterized by the major peaks in the followingX-ray powder diffraction pattern
Peak no. 1 2 3 4 5 6 7 8 2SÇ°) 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(e) Cu 8.7 21.0 22.0 24.2 24.2 26.6 27.2 d soace 4.7 4.2 4.0 3.7 3.7 3.5 3.3
The novel crystal form of 7-([1o,5a,6a]-6-amino-3-azabicyclo[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 sait (hereinafter "the anhydrate") is hydrophobically stable andcharacterized by the major peaks in the following X-ray powder diffraction pattern. -3-
Peak no. 1 2 3 4 5 6 7 8 2β(°) 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 5 The anhydrate may be prepared by heating 7-([lCT,5a,6a]-6-amino-3- azabicyclo[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 sait or its derived monohydratein an organic solvent or a mixture thereof with an aprotic co-solvent, such asisopropanol, dimethylsulfoxide, n-propanol, tetrahydrofuran or n-butanol, preferably 1 O n-butanol or tetrahydrofuran/n-butanol, to reflux or to a température between about7C°C to about 90°C, preferably about 85°C. Depending on the reaction températureand other conditions, the reaction time generally ranges from about 1 hour to about 20hcnurs, preferably about 2 hours to about 16 hours.
The crystal slurry formed is cooled to a température between about 20°C to 15 about 30°C, preferably about 25°C, for a time period between about 2 hours to about24 hours, preferably about 2 hours to about 12 hours. The crystalline product is thenfiltered from the mother liquid and dried under vacuum until ail the solvent has beenremoved.
The anhydrate may be administered as an antibacterial agent as described in 2C above-mentioned United States Patent No. 5,229,396. Administration to a subject maybe alone, but the anhydrate will generally be administered in admixture with apharmaceutical carrier selected with regard to the intended route of administration andstandard pharmaceutical practice. For example, it can be administered orally or in theform of tablets containing such excipients as starch or lactose, or in capsules either 25 alone or in admixture with excipients, or in the form of élixirs or suspensions containingfiavoring or coloring agents. In the case of animais, it is advantageously contained inan animal feed.
The invention also provides pharmaceutical compositions comprising anantibacterially effective amount of the anhydrate together with a pharmaceutically 30 acceptable diluent or carrier.
The anhydrate can be administered to humans for the treatment of bacterialdiseases by either the oral or parentéral routes, and may be administered orally atdosage levels of about 0.1 to 500 mg/kg/day, advantageously 0.5-50 mg/kg/day given -4- 010293 in a single dose or up to 3 divided doses. For intramuscular or intravenousadministration, dosage levels are about 0.1-200 mg/kg/day, advantageously 0.5-50mg/kg/day. While intramuscular administration may be a single dose or up to 3 divideddoses, intravenous administration can include a continuous drip. Variations will 5 necessarily occur depending on the weight and condition of the subject being treatedand the particular route of administration chosen as will be known to those skilled in theart.
The antibacterial activity of the anhydrate is shown by testing according to theSteer's replicator technique which is a standard in vitro bacterial testing method 10 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 '•,5 7-ff1g.5g,6o1-e-amino-3-azabicvclor3.1.01hex-3-vl)-6-fluoro-1- (2,4-<iifluorophenvl)-1.4-dihvdro-4-oxo-1.8-naphthvridine-3-carboxvlic acid, methanesulfonic acid sait 7-([1a, 5a, 6o]-6-tert-butyloxycarbonylamino-3-azabicyclo]3,1,0]hex-3yl)-6-fluoro-1 (2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.ethylester, 20 (25 g) and methanesulfonic acid (11 g) was added to a mixture of water (250 mL) and teferahydrofuran (250 mL). The résultant slurry was heated to reflux (about 66°C)température and held at this température for 20 hours after which time a clear solutionwas obtained. The solution was cooled to 35-40°C and concentrated under reducedpressure to about half its original volume. The résultant crystal slurry was cooled 25 slowly to room température (about 20°C) and then further stirred at 10°C for 2 hours.The crystalline product 7-([1a,5a,6cr]-6-amino-3-azabicyclo[3.1.0]hex-3-yl)-6-fluoro-1-(2,-*-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,metthanesulfonic acid sait was isolated by filtration and washed with a mixture oftetrahydrofuran (12.5 mL) and water (12.5 mL). The crystals were dried under vacuum 30 at 30-35° until the residual water content of the crystals was below 0.2%. Yield 21.2g, 90%.
The crystals of 7-([1o,5o,6o]-6-amino-3-azabicyclo[3 1,0]hex-3-yl)-6-fluoro-
-5- 1 -(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,methanesulfonic acid sait are characterized by the major peaks in the following X-raypowder 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-([lCT,5ûr,6ff]-6-amino-3-azabicyclo[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 sait can pick up water from the atmosphère and form amonohydrate. The monohydrate is characterized by the major peaks in the followingX-ray powder diffraction pattern.
Peak no. 1 2 3 4 5 6 7 8 2fl(°) Cu 4.7 9.4 12.4 13.1 13.6 14.2 17.0 17.9 c 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 Z0(°) 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
Example 1 7-(f1o, 5o, 6g1-6-amino-3-azabicyclor3.,1.01hex-3v)-6-fluoro-1-(2.4- difluorophenvh-1,4-dihydro-4-oxo-1.8-naphthyridine-3-carboxylic acid, methanesulfonic acid sait anhydrous 7-([1o,5o,6a]-6-amino-3-azabicyclo[3.1,0]hex-3-yl)-6-fluoro-1 -(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid .methanesulfonicacid sait or its monohydrate (20 g) was stirred with isopropanol (220 ml). The crystalsuspension was refluxed for 16 hours or until microscopie examination had shown thatthe crystal form had changed to a hexagonal form. The crystal slurry was cooled to 20-25°C and stirred at this température for about 1 hour. The crystalline product wasfiltered from the mother liquor, washed with isopropanol (about 50 mL) and dried undervacuum at 40°C until ail the solvent had been removed. Yield 98%. 010293
The product is a new polymorphie form of 7-((1 σ,5σ,6o]-6-amino-3-azabicyclo[3.1,0]hex-3-yl)-6-fluoro-1 -(2,4-difluorophenyl)-l ,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonic acid sait, anhydrous, characterizedby 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 10 Nflft 5a, 6gl-6-amino-3-azabicyclof3.1.01hex-3v)-g-fluoro-1-(2,4- difluorophenvl)-1.4-dihvdro-4-oxo-1.8-naphthyridine-3-carboxylic acid, methanesulfonic acid sait anhydrous 7-((1 o,5o,6cr]-6-amino-3-azabicyclo[3.1.0]hex-3-y l)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,methanesulfonic 15 acid sait or its monohydrate (7 g) was dissolved in dimethylsulfoxide, DMSO (21 ml_)by heating to 80-85°C until complété solution was obtained. Isopropanol (150 ml_) wasadded dropwise to the solution at about 85°C to induce crystallization. The crystalsuspension was held at reflux température about 85°C for 2-16 hours or untilmicroscopie examination had shown that the crystal form had changed to a hexagonal 20 form. The résultant crystal slurry was cooled to 20-25°C, The crystalline product wasfiltered from the mother liquor, washed with isopropanol (about 50 mL) and dried undervacuum at 50°C until ail the solvents had been removed. Yield 77%.
The product is the same as in Example 1.
Example 3 25 7-(Γ1σ, 5g, 6ql-6-amino-3-azabicyciof3.1.0lhex-3y)-6-fluoro-1 -(2,4- difluorophenyl)-1.4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonic acid sait, anhydrous 7-((1 a,5a,6o]-6-amino-3-azabicyclo(3.1,0]hex-3-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,methanesulfonic 30 acid sait or its monohydrate (55.6 g) was dissolved in dimethylsulfoxide, DMSO (159mL) by heating to 80-85°C until complété solution was obtained. The solution wascoofed to 20-25°C and stirred for 2 hours until a crystal slurry formed. -7- ο ί 0293
Dichioromethane (1200 mL) was added dropwise to the solution at about 25°C to fullyinduce crystallization. The crystal suspension was held at room température ovemightor until microscopie examination had shown that the crystal form had changed to ahexagonal form. The crystalline product was filtered fronrt the mother liquor, washed 5 with dichioromethane (3x119 mL) and dried under vacuum at 50°C until ail the solventhad been removed. Yield91%.
The product is the same as in Example 1.
Example 4 7-(H a, 5σ, 6g1-6-amino-3-azabicyclor3.1.01hex-3y)-6-fluoro-1 -(2,4- 10 difluorophenyO-1.4-dihvdro-4-oxo-1.8-naphthyridine-3-carboxylic acid, methanesulfonic acid sait anhydrous 7-([1a,5a,6a]-6-amino-3-azabicyclo[3.1.0]hex-3-yl)-6-fluoro-1 -(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,methanesulfonicacid sait or its monohydrate (1 g) was stirred with n-propanol (44 mL). The crystal 15 suspension was refluxed for 3 hours or until microscopie examination had shown thatthe crystal form had changed to a hexagonal form. The crystal slurry was cooled at 20-25°C and stirred ovemight. 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 ail thesolvent had been removed. Yield 68%. 20 The product is the same as in Example 1.
Example 5 7-(Γ1ο, 5σ, 6o1-6-amino-3-azabicyclor3.1.0fhex-3y)-6-fluoro-1 -(2,4- difluoropheny Π-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonic acid sait anhydrous 25 7-([1g,5g,6o]-6-amino-3-azabicyclo[3.1,0]hex-3-yl)-6-fluoro-1 -(2,4- difSuorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,methanesulfonicacad sait or its monohydrate (70 g) was stirred with a mixture of tetrahydrofuran (175mL) and a n-butanol (525 mL). The crystal suspension was heated for 16 hours or untilmicroscopie examination had shown that the crystal form had changed to a hexagonal 30 form. The crystal slurry was cooled to 20-25°C and stirred ovemight. 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 ail the solvent had been removed. Yield 95%. -8- υ 1 02 9 3
The product is the same as in Example 1.
Example 6 7-(pi a, 5a, 6a1-6-amîno-3-azabicyclof3.1.0lhex-3v)-6-fluoro-1 -(2,4- difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 5 methanesulfonic acid sait anhydrous 7-([1ff,5a,6e]-6-amino-3-azabicyclo[3.1,0]hex-3-yl)-6-fluoro-1 -(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid .methanesulfonicacid sait 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 microscopie 10 examination had shown that the crystal form had changed to a hexagonal form. Thecrystal slurry was cooled to 20-25°C and stirred overnight. The crystalline product wasfiitered from the mother liquor, washed with n-butanol (about 20 mL) and dried undervacuum at 50-55°C until ail the solvent had been removed. Yield 92%.
The product is the same as in Example 1.
Claims (3)
- 9 v 1 Ο 2 3 3 PLAINS 1. α ,5α»6ûc/-6 -amino-3-azabicyclo^3.1.o7hex-5-yl ) -6-fluoro-1-(2,4-dif luorophenyl ) -1,4-dihy dro-4-oxo-Ί,8-naphthyridine-3-carboxylic acid, methanesuifonic acid 5 sait characterized by the following major peaks in its X-raypowder diffraction pattern J Peak no. t « ! 1 ! 1 2 ' 5 ! î 4 1 5 s 6 ! ? ί t • 8 I • ! ; ! ! t • ! I l « î • ! -l· ! ! ! î i r • I ! ! 20(°) Cu t 4. 5 t 7.7 9.1 i 13.6! 15.0! 18.2! 18.6! 22.8 t 1 î i ! ! ! j ! 1 j 1 1 ! î I t « t ! ! d space 1 * i 19. 5 t 11.5 9.7 I 6.5! 5.9! 4.9! 4.8! ! 3.9 t i i ! I ! ! t • î * ΙΟ
- 2. A pharmaceutical composition having antibacterial acmiviry comprising the compound according to claim 1 in an amouneffective in the treatment of a bacterial infection, and a pharma·ceurically acceptable carrier.
- 3. A process for preparing the compound according to '5 claim 1, vmich comprises heating 7- (^û-,5ol,6o7- 6-amino-3- azacicyc îafj.i •O/hex-J-yl ) —6—fluoro—1—(2,4-difluorophenyl ) -1,4—iihydro-4— oxo-1,8-naphthyridine-3-carboxylic acid, metha-nesuifonic acid sait or its derived monohydrate in the presenceof an. alcohol or mixture thereof with an aprotic co-solvent.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US1995/007211 WO1996039406A1 (fr) | 1995-06-06 | 1995-06-06 | NOUVELLE FORME DE CRISTAL DE SEL ANHYDRE D'ACIDE METHANE-SULFONIQUE ET D'ACIDE 7-([1α, 5α, 6α]-6-AMINO-3-AZABICYCLO[3.1.0]HEX-3-YL)-6-FLUORO-1-(2,4-DIFLUOROPHENYL)-1,4-DIHYDRO-4-OXO-1,8-NAPHTYRIDINE-3 CARBOXYLIQUE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| OA10293A true OA10293A (en) | 1997-09-19 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| OA60835A OA10293A (en) | 1995-06-06 | 1996-06-06 | Novel crystal form of anhydrous 7-(Ä1alpha, 5alpha, 6alphaÜ-6-amino-3-azabicyclo Ä3.1.0Ü hex-3-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4- dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid methanesulfonic acid salt |
Country Status (38)
| Country | Link |
|---|---|
| US (1) | US5763454A (fr) |
| EP (1) | EP0789697B1 (fr) |
| JP (1) | JP3145715B2 (fr) |
| KR (1) | KR100191989B1 (fr) |
| CN (1) | CN1055474C (fr) |
| AR (1) | AR002753A1 (fr) |
| AU (1) | AU703634B2 (fr) |
| BG (1) | BG62443B1 (fr) |
| BR (1) | BR9602630A (fr) |
| CA (1) | CA2223404C (fr) |
| CZ (1) | CZ285878B6 (fr) |
| DE (1) | DE69503066T2 (fr) |
| DK (1) | DK0789697T3 (fr) |
| DZ (1) | DZ2046A1 (fr) |
| ES (1) | ES2117426T3 (fr) |
| FI (1) | FI974441A0 (fr) |
| HR (1) | HRP960267B1 (fr) |
| HU (1) | HUP9601540A3 (fr) |
| IL (1) | IL118488A (fr) |
| IS (1) | IS4351A (fr) |
| LV (1) | LV11619B (fr) |
| MA (1) | MA23892A1 (fr) |
| NO (1) | NO305599B1 (fr) |
| NZ (1) | NZ286735A (fr) |
| OA (1) | OA10293A (fr) |
| PE (1) | PE38097A1 (fr) |
| PL (1) | PL314604A1 (fr) |
| RU (1) | RU2125571C1 (fr) |
| SG (1) | SG54339A1 (fr) |
| SI (1) | SI9600185A (fr) |
| SK (1) | SK280535B6 (fr) |
| TN (1) | TNSN96084A1 (fr) |
| TW (2) | TW580389B (fr) |
| UA (1) | UA44718C2 (fr) |
| UY (1) | UY25459A1 (fr) |
| WO (1) | WO1996039406A1 (fr) |
| YU (1) | YU34596A (fr) |
| ZA (1) | ZA964647B (fr) |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020032216A1 (en) | 1997-03-21 | 2002-03-14 | Lg Chemical Ltd. | Salt of naphthyridine carboxylic acid derivative |
| MA24500A1 (fr) | 1997-03-21 | 1998-10-01 | Lg Life Sciences Ltd | Derive du sel d'acide carboxylique de naphthyridine . |
| HN1998000106A (es) | 1997-08-01 | 1999-01-08 | Pfizer Prod Inc | Composiciones parenterales de alatroflaxacino |
| DE19800214A1 (de) | 1998-01-06 | 1999-07-15 | Knoll Ag | Verfahren zur Herstellung von Doxazosin-Mcsylat in einer als Form A bezeichneten Kristallmodifikation und ein Zwischenprodukt dafür |
| US7019142B2 (en) * | 1998-01-16 | 2006-03-28 | Pfizer Inc. | Process for preparing naphthyridones and intermediates |
| GB9818258D0 (en) * | 1998-08-21 | 1998-10-14 | Pfizer Ltd | Antifungal compositions |
| HN1999000141A (es) * | 1998-09-03 | 2000-06-19 | Pfizer Prod Inc | Procedimiento para preparar sales de trovafloxacina de adicion de acidos. |
| GB9820405D0 (en) * | 1998-09-18 | 1998-11-11 | Smithkline Beecham Plc | Process |
| ES2164520B1 (es) * | 1999-03-16 | 2003-04-01 | Medichem Sa | "procedimiento de obtencion del polimorfo a del mesilato de doxazosina" |
| US6239141B1 (en) | 1999-06-04 | 2001-05-29 | Pfizer Inc. | Trovafloxacin oral suspensions |
| GB9920917D0 (en) | 1999-09-03 | 1999-11-10 | Sb Pharmco Inc | Novel process |
| GB9920919D0 (en) | 1999-09-03 | 1999-11-10 | Sb Pharmco Inc | Novel compound |
| US6596871B2 (en) | 2001-06-29 | 2003-07-22 | Grayson Walker Stowell | Polymorphic forms of 6-[4-(1-cyclohexyl-1h-tetraol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone |
| US6660864B2 (en) | 2001-06-29 | 2003-12-09 | Grayson Walker Stowell | Polymorphic forms of 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone |
| US6573382B2 (en) | 2001-06-29 | 2003-06-03 | Grayson Walker Stowell | Polymorphic forms of 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone |
| US6388080B1 (en) | 2001-06-29 | 2002-05-14 | Grayson Walker Stowell | Polymorphic forms of 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone |
| US6531603B1 (en) | 2001-06-29 | 2003-03-11 | Grayson Walker Stowell | Polymorphic forms of 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone |
| US6657061B2 (en) | 2001-06-29 | 2003-12-02 | Grayson Walker Stowell | Polymorphic forms of 6-[4-1(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone |
| KR100517638B1 (ko) | 2002-04-08 | 2005-09-28 | 주식회사 엘지생명과학 | 게미플록사신 산염의 새로운 제조방법 |
| CN102512364A (zh) * | 2011-12-30 | 2012-06-27 | 天津市嵩锐医药科技有限公司 | 一种供注射用的甲磺酸阿拉曲伐沙星药物组合物 |
| WO2014109376A1 (fr) * | 2013-01-11 | 2014-07-17 | 参天製薬株式会社 | Bouchon intérieur, réceptacle pour liquide muni dudit bouchon intérieur, structure de pointe de buse, et réceptacle pour liquide muni de ladite structure |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5164402A (en) * | 1989-08-16 | 1992-11-17 | Pfizer Inc | Azabicyclo quinolone and naphthyridinone carboxylic acids |
| WO1991002526A1 (fr) * | 1989-08-16 | 1991-03-07 | Pfizer Inc. | Acides azabicyclo quinolone carboxyliques |
| CZ286896B6 (en) * | 1994-01-18 | 2000-07-12 | Pfizer | Process for preparing pharmaceutically acceptable salts of naphthyridone carboxylic acid and intermediates for this preparation |
| GB2289674A (en) * | 1994-05-23 | 1995-11-29 | Pfizer | Antibacterial naphthyridine |
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1995
- 1995-06-06 DK DK95922240T patent/DK0789697T3/da active
- 1995-06-06 US US08/849,300 patent/US5763454A/en not_active Expired - Fee Related
- 1995-06-06 SK SK719-96A patent/SK280535B6/sk unknown
- 1995-06-06 WO PCT/US1995/007211 patent/WO1996039406A1/fr not_active Ceased
- 1995-06-06 CA CA002223404A patent/CA2223404C/fr not_active Expired - Fee Related
- 1995-06-06 DE DE69503066T patent/DE69503066T2/de not_active Expired - Fee Related
- 1995-06-06 JP JP50037497A patent/JP3145715B2/ja not_active Expired - Fee Related
- 1995-06-06 FI FI974441A patent/FI974441A0/fi unknown
- 1995-06-06 ES ES95922240T patent/ES2117426T3/es not_active Expired - Lifetime
- 1995-06-06 EP EP95922240A patent/EP0789697B1/fr not_active Expired - Lifetime
-
1996
- 1996-05-13 TW TW089107609A patent/TW580389B/zh not_active IP Right Cessation
- 1996-05-13 TW TW085105632A patent/TW403751B/zh not_active IP Right Cessation
- 1996-05-29 CN CN96110060A patent/CN1055474C/zh not_active Expired - Fee Related
- 1996-05-30 IL IL11848896A patent/IL118488A/en not_active IP Right Cessation
- 1996-05-31 AR ARP960102817A patent/AR002753A1/es unknown
- 1996-06-03 IS IS4351A patent/IS4351A/is unknown
- 1996-06-04 BR BR9602630A patent/BR9602630A/pt not_active Application Discontinuation
- 1996-06-04 LV LVP-96-172A patent/LV11619B/en unknown
- 1996-06-04 UA UA96062190A patent/UA44718C2/uk unknown
- 1996-06-04 PL PL96314604A patent/PL314604A1/xx unknown
- 1996-06-05 NO NO962321A patent/NO305599B1/no not_active IP Right Cessation
- 1996-06-05 RU RU96111026A patent/RU2125571C1/ru not_active IP Right Cessation
- 1996-06-05 NZ NZ286735A patent/NZ286735A/en unknown
- 1996-06-05 MA MA24262A patent/MA23892A1/fr unknown
- 1996-06-05 AU AU54749/96A patent/AU703634B2/en not_active Ceased
- 1996-06-05 HU HU9601540A patent/HUP9601540A3/hu unknown
- 1996-06-05 CZ CZ961625A patent/CZ285878B6/cs not_active IP Right Cessation
- 1996-06-05 DZ DZ960090A patent/DZ2046A1/fr active
- 1996-06-05 ZA ZA9604647A patent/ZA964647B/xx unknown
- 1996-06-05 BG BG100639A patent/BG62443B1/bg unknown
- 1996-06-05 KR KR1019960020171A patent/KR100191989B1/ko not_active Expired - Fee Related
- 1996-06-05 SG SG1996009972A patent/SG54339A1/en unknown
- 1996-06-05 YU YU34596A patent/YU34596A/sh unknown
- 1996-06-05 TN TNTNSN96084A patent/TNSN96084A1/fr unknown
- 1996-06-06 PE PE1996000421A patent/PE38097A1/es not_active Application Discontinuation
- 1996-06-06 OA OA60835A patent/OA10293A/fr unknown
- 1996-06-06 HR HR960267A patent/HRP960267B1/xx not_active IP Right Cessation
- 1996-06-06 SI SI9600185A patent/SI9600185A/sl not_active IP Right Cessation
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1999
- 1999-04-06 UY UY25459A patent/UY25459A1/es not_active Application Discontinuation
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