WO1996039406A1 - NOVEL CRYSTAL FORM OF ANHYDROUS 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-NAPHTHYRIDINE-3-CARBOXYLIC ACID, METHANESULFONIC ACID SALT - Google Patents

NOVEL CRYSTAL FORM OF ANHYDROUS 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-NAPHTHYRIDINE-3-CARBOXYLIC ACID, METHANESULFONIC ACID SALT Download PDF

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Publication number
WO1996039406A1
WO1996039406A1 PCT/US1995/007211 US9507211W WO9639406A1 WO 1996039406 A1 WO1996039406 A1 WO 1996039406A1 US 9507211 W US9507211 W US 9507211W WO 9639406 A1 WO9639406 A1 WO 9639406A1
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WO
WIPO (PCT)
Prior art keywords
naphthyridine
oxo
fluoro
amino
difluorophenyl
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PCT/US1995/007211
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French (fr)
Inventor
Lynne A. Handanyan
Thomas A. Morris
Robert L. Hendrickson
Phillip J. Johnson
Timothy Norris
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Pfizer Inc
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Pfizer Inc
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Priority to PCT/US1995/007211 priority Critical patent/WO1996039406A1/en
Priority to US08/849,300 priority patent/US5763454A/en
Priority to ES95922240T priority patent/ES2117426T3/en
Priority to SK719-96A priority patent/SK280535B6/en
Priority to EP95922240A priority patent/EP0789697B1/en
Priority to JP50037497A priority patent/JP3145715B2/en
Priority to MXPA/A/1997/009873A priority patent/MXPA97009873A/en
Priority to CA002223404A priority patent/CA2223404C/en
Priority to DE69503066T priority patent/DE69503066T2/en
Priority to DK95922240T priority patent/DK0789697T3/en
Priority to FI974441A priority patent/FI974441L/en
Priority to TW085105632A priority patent/TW403751B/en
Priority to TW089107609A priority patent/TW580389B/en
Priority to CN96110060A priority patent/CN1055474C/en
Priority to IL11848896A priority patent/IL118488A/en
Priority to ARP960102817A priority patent/AR002753A1/en
Priority to IS4351A priority patent/IS4351A/en
Priority to LVP-96-172A priority patent/LV11619B/en
Priority to UA96062190A priority patent/UA44718C2/en
Priority to BR9602630A priority patent/BR9602630A/en
Priority to PL96314604A priority patent/PL314604A1/en
Priority to BG100639A priority patent/BG62443B1/en
Priority to ZA9604647A priority patent/ZA964647B/en
Priority to RU96111026A priority patent/RU2125571C1/en
Priority to SG1996009972A priority patent/SG54339A1/en
Priority to HU9601540A priority patent/HUP9601540A3/en
Priority to MA24262A priority patent/MA23892A1/en
Priority to YU34596A priority patent/YU34596A/en
Priority to KR1019960020171A priority patent/KR100191989B1/en
Priority to CZ961625A priority patent/CZ285878B6/en
Priority to TNTNSN96084A priority patent/TNSN96084A1/en
Priority to AU54749/96A priority patent/AU703634B2/en
Priority to NO962321A priority patent/NO305599B1/en
Priority to NZ286735A priority patent/NZ286735A/en
Priority to DZ960090A priority patent/DZ2046A1/en
Priority to HR960267A priority patent/HRP960267B1/en
Priority to SI9600185A priority patent/SI9600185A/en
Priority to PE1996000421A priority patent/PE38097A1/en
Priority to OA60835A priority patent/OA10293A/en
Publication of WO1996039406A1 publication Critical patent/WO1996039406A1/en
Anticipated expiration legal-status Critical
Priority to UY25459A priority patent/UY25459A1/en
Ceased legal-status Critical Current

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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
    • 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

  • the invention is directed to a novel crystal form of anhydrous 7-([1 ⁇ ,5 ⁇ ,6 ⁇ ]-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, methanesulfonio 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.
  • the invention is directed to a novel crystal form of anhydrous 7-([1 ⁇ ,5 ⁇ ,6 ⁇ ]-6- _mino-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, methanesulfonio 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.
  • the monohydrate 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
  • the novel crystal form of 7-([1 ⁇ ,5 ⁇ ,6 ⁇ ]-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, methanesulfonio acid salt (hereinafter "the anhydrate”) is hydrophobically stable and characterized by the major peaks in the following X-ray powder diffraction pattern. Peak no. 1 2 3 4 5 6 7 8
  • the anhydrate may be prepared by heating 7-([1 ⁇ ,5 ⁇ ,6 ⁇ ]-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, methanesulfonio 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.
  • the reaction time generally ranges from about 1 hour to about 20 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.
  • a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • 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.
  • it is advantageously contained in an animal feed.
  • the invention also provides pharmaceutical compositions comprising an antibacterially 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 in a single dose or up to 3 divided doses.
  • 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 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).
  • 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-([1 ⁇ ,5 ⁇ ,6 ⁇ ]-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-carboxylicacid, methanesulfonio acid salt was isolated by filtration and washed with a mixture of tetrahydrofuran (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-([1 ⁇ ,5 ⁇ ,6 ⁇ ]-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, methanesulfonio 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.
  • Example 1 7-(M ⁇ . 5 ⁇ . 6 ⁇ l-6-amino-3-azabicvclor3.1.01hex-3v)-6-fluoro-1-(2.4- difluorophenyl)-1 .4-dihvdro-4-oxo-1 ,8-naphthyridine-3-carboxylic acid, methanesulfonio acid salt, anhydrous
  • 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%.
  • the product is a new polymorphic form of 7-([1 ⁇ ,5 ⁇ ,6 ⁇ ]-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, methanesulfonio acid salt, anhydrous, characterized by the following major peaks in its X-ray powder diffraction pattern.
  • Example 2 7-fM ⁇ . 5 ⁇ . 6 ⁇ 1-6-amino-3-azabicvclor3.1.0lhex-3y)-6-fluoro-1-(2.4- difluorophenyl)-1.4-dihvdro-4-oxo-1 ,8-naphthyridine-3-carboxylic acid, methanesulfonio acid salt, anhydrous
  • 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-(M a. 5a. 6crl-6-amino-3-azabicvclor3.1.01hex-3v>-6-fluoro-1 -(2.4- difluorophenvO-1 .4-dihvdro-4-oxo-1 .8-naphthyridine-3-carboxylic acid, methanesulfonio acid salt, anhydrous
  • Example 4 7-(H ⁇ . 5 ⁇ . 6ff1-6-amino-3-azabicvclo[3.1.0lhex-3v)-6-fluoro-1-(2.4- difluorophenyl)-1 ,4-dihvdro-4-oxo-1 ,8-naphthyridine-3-carboxylic acid. methanesulfonio acid salt, anhydrous
  • Example 5 The product is the same as in Example 1.
  • Example 5 The product is the same as in Example 1.
  • Example 5 The product is the same as in Example 1.
  • Example 6 7-(M . 5 ⁇ . ⁇ 1-6-amino-3-azabicvclor3.1.01hex-3v)- ⁇ -fluoro-1-(2.4- difluorophenvD-1.4-dihvdro-4-oxo-1.8-naphthyridine-3-carboxylic acid, methanesulfonio acid salt, anhydrous 7-([1 ⁇ ,5 ⁇ ,6 ⁇ ]-6-amino-3-azabicyclo [3.1.0]hex-3-yl)-6-fluoro-1 -(2,4-difluorophenyl)-

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  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

The anhydrate of 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-naphthyridine-3-carboxylic acid, methanesulfonic acid salt has advantageous stability for formulation as an antibacterial agent.

Description

NOVEL CRYSTAL FORM OF ANHYDROUS 7-(f1 .5q.6σ1-6-AMINO-3-
AZABICYCLOr3.1.01HEX-3-YU-6-FLUORO-1 -(2.4-DIFLUOROPHENYU-1.4- DIHYDRO-4-OXO-1.8-NAPHTHYRIDINE-3-CARBOXYLIC ACID. METHANESULFONIC ACID SALT Background 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, methanesulfonio 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-([1 σ,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-carboxylicacid, methanesulfonio acid salt of the formula
Figure imgf000003_0001
wherein Y is o,p-difluorophenyl and R2 is
Figure imgf000003_0002
I I having antibacterial activity. Summarv of the Invention The invention is directed to a novel crystal form of anhydrous 7-([1 σ,5σ,6σ]-6- _mino-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, methanesulfonio 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-([1 σ,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, methanesulfonio 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 1 2 3 4 5 6 7 8 9 10 no.
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
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 18.7 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 18.7 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-([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, methanesulfonio acid salt (hereinafter "the anhydrate") is hydrophobically stable and 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 4.5 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-([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, methanesulfonio 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 antibacterially 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 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 q,5g.6or1-6-amino-3-azabicyclor3.1.01hex-3-yl)-6-fluoro-1 -
(2.4-dif luorophenyl>-1 ,4-dihvdro-4«oxo-1 ,8-naphthyridine-3-carboxylic acid. methanesulfonio acid salt
7-([1σ,5σ,6σ]-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-carboxylicacid, ethyl ester, (25 g) and methanesulfonio acid (11 g) was added to a mixture of water (250 mL) and tetrahydrofuran (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-([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-carboxylicacid, methanesulfonio acid salt was isolated by filtration and washed with a mixture of tetrahydrofuran (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-([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, methanesulfonio acid salt are characterized by the major peaks in the following X-ray powder diffraction pattern.
Peak 1 2 3 4 5 6 7 8 9 10 no.
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-([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, methanesulfonio 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 18.7 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 18.7 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-(M σ. 5σ. 6σl-6-amino-3-azabicvclor3.1.01hex-3v)-6-fluoro-1-(2.4- difluorophenyl)-1 .4-dihvdro-4-oxo-1 ,8-naphthyridine-3-carboxylic acid, methanesulfonio acid salt, 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, methanesulfonio acid salt or its monohydrate (20 g) was stirred with isopropanol (220 ml). The crystal suspension was refiuxed 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 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%. The product is a new polymorphic form of 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, methanesulfonio 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 19.5 11.5 9.7 6.5 5.9 4.9 4.8 3.9
Example 2 7-fM α. 5σ. 6σ1-6-amino-3-azabicvclor3.1.0lhex-3y)-6-fluoro-1-(2.4- difluorophenyl)-1.4-dihvdro-4-oxo-1 ,8-naphthyridine-3-carboxylic acid, methanesulfonio acid salt, anhydrous
7-([1 σ,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, methanesulfonio 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-(M a. 5a. 6crl-6-amino-3-azabicvclor3.1.01hex-3v>-6-fluoro-1 -(2.4- difluorophenvO-1 .4-dihvdro-4-oxo-1 .8-naphthyridine-3-carboxylic acid, methanesulfonio acid salt, 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, methanesulfonio 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. Dichloromethane (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 dichloromethane (3 x 119 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-(Hσ. 5σ. 6ff1-6-amino-3-azabicvclo[3.1.0lhex-3v)-6-fluoro-1-(2.4- difluorophenyl)-1 ,4-dihvdro-4-oxo-1 ,8-naphthyridine-3-carboxylic acid. methanesulfonio acid salt, anhydrous
7-([1 αr,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, methanesulfonio 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 20-25°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-(M a. 5σ. 6flrl-6-amino-3-azabicyclor3.1 -01hex-3v)-6-f luoro-1 -(2.4- dif luorophenyD-1.4-dihvdro-4-oxo-1 ,8-naphthyridine-3-carboxylic acid, methanesulfonio acid salt, anhydrous
7-([1σ,5σ,6σ]-6-amino-3-azabicyclo[3.1.0]hex-3-yl)-6-fiuoro-1-(2,4-difluorophenyl)- 1 ,4-dihydro-4-oxo-1 ,8-naphthyridine-3-carboxylic acid, methanesulfonio 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%.
The product is the same as in Example 1. Example 6 7-(M . 5σ. β 1-6-amino-3-azabicvclor3.1.01hex-3v)-β-fluoro-1-(2.4- difluorophenvD-1.4-dihvdro-4-oxo-1.8-naphthyridine-3-carboxylic acid, methanesulfonio acid salt, anhydrous 7-([1 σ,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, methanesulfonio 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 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

CLAIMS 1. 7-([1σ,5σ,6σ]-6-amino-3-azabicyclo[3.1.0]hex-3-yl)-6-fluoro-1 -(2I4- difluorophenyl)-1 ,4-dihydro-4-oxo-1 ,8-naphthyridine-3-carboxylicacid, methanesulfonio acid salt 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 19.5 11.5 9.7 6.5 5.9 4.9 4.8 3.9
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 to claim 1.
4. A process for preparing the compound according to claim 1 , which comprises heating 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-carboxylicacid, methanesulfonio acid salt or its derived monohydrate in the presence of an alcohol or mixture thereof with an aprotic co-solvent.
PCT/US1995/007211 1995-06-06 1995-06-06 NOVEL CRYSTAL FORM OF ANHYDROUS 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-NAPHTHYRIDINE-3-CARBOXYLIC ACID, METHANESULFONIC ACID SALT Ceased WO1996039406A1 (en)

Priority Applications (40)

Application Number Priority Date Filing Date Title
PCT/US1995/007211 WO1996039406A1 (en) 1995-06-06 1995-06-06 NOVEL CRYSTAL FORM OF ANHYDROUS 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-NAPHTHYRIDINE-3-CARBOXYLIC ACID, METHANESULFONIC ACID SALT
US08/849,300 US5763454A (en) 1995-06-06 1995-06-06 Crystal form of anhydrous 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 naphthyridine-3-carboxylic acid, methanessulfonic acid salt
ES95922240T ES2117426T3 (en) 1995-06-06 1995-06-06 CRYSTALLINE FORM OF ANHYDRAUS SALT COMPOSED OF ACIDS 7 - ((1A, 5A, 6A) -6-AMINO-3-AZABICICLO (3.1.0.) HEX-3-IL) -6-FLUORO-1- (2, 4-DIFLUOROFENIL) -1,4-DIHIDRO-4-OXO-1,8-NAFTIRIDINA-3-CARBOXILICO AND METANOSULFONICO.
SK719-96A SK280535B6 (en) 1995-06-06 1995-06-06 CRYSTAL FORM OF ACID 7 - ([1A, 5A
EP95922240A EP0789697B1 (en) 1995-06-06 1995-06-06 CRYSTAL FORM OF 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, METHANESULFONIC ACID SALT
JP50037497A JP3145715B2 (en) 1995-06-06 1995-06-06 Anhydrous 7-([1α, 5α, 6α] -6-amino-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- (2,4-difluorophenyl) -1, Novel crystalline form of 4-dihydro-4-oxo-1,8-naphthyridin-3-carboxylic acid methanesulfonate
MXPA/A/1997/009873A MXPA97009873A (en) 1995-06-06 1995-06-06 New crystaline form of acid 7 ([1alfa, 5alfa6alfa] -6-amino-3-azabiciclo [3.1.0] hex-3-il) -6-fluor-1- (2,4-difluorofenil) 1,4-dihydro -4-oxo-1,8-naftiridin-3-carboxilico anihdro, salt of acidomethane-sulfonico, compositions that contains it
CA002223404A CA2223404C (en) 1995-06-06 1995-06-06 Novel crystal form of anhydrous 7-(¬1.alpha., 5.alpha., 6.alpha.|-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 salt
DE69503066T DE69503066T2 (en) 1995-06-06 1995-06-06 CRYSTAL FORM OF WATER-FREE 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 CARBONIC ACID METHANESULFONIC ACID SALT
DK95922240T DK0789697T3 (en) 1995-06-06 1995-06-06 Crystal form of anhydrous 7 - ([1alpha, 5alpha, 6alpha,] - 6-amino-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- (2,4-difluorophenyl) -1, 4-d
FI974441A FI974441L (en) 1995-06-06 1995-06-06 A new crystal form of the methanesulfonic acid salt of anhydrous 7-((1alpha,5alpha,6alpha)-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
TW085105632A TW403751B (en) 1995-06-06 1996-05-13 Novel crystal form of anhydrous 7-([1<alpha>, 5<alpha>,6<alpha>,]-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 salt
TW089107609A TW580389B (en) 1995-06-06 1996-05-13 Pharmaceutical composition having antibacterial activity
CN96110060A CN1055474C (en) 1995-06-06 1996-05-29 Noval crystal type anhydrous 7-([1 alpha, 5 alpha, 6 alpha]-6-amino-3-azabicyclo[3,1,0]hexyl-3-group)-6-fluorine-1-(2,4-difluorophenyl
IL11848896A IL118488A (en) 1995-06-06 1996-05-30 Hexagonal crystal form of anhydrous 7-([1alpha,5alpha,6alpha]-6-amino-3- azabicyclo [3.1.0] hex-3-yl)-6-fluoro-1- (2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthydridine-3-carboxylic acid, methanesulfonic acid salt its preparation and antibacterial pharmaceutical compostions containing it
ARP960102817A AR002753A1 (en) 1995-06-06 1996-05-31 ACID 7 - ([[ALPHA, 5 ALPHA, 6 ALPHA] -6-AMINO-3-AZABICICLO [3.1.0] HEX-3-IL) -6- FLUOR-1- (2,4-DIFLUOROPHENYL) -1 , 4-DIDHIRO-4-OXO-1,8-NAFTIRIDIN-3-CARBOXILICO, SALDEL METANOSULFONICO ACID, A PROCEDURE TO PREPARE IT AND A PHARMACEUTICAL COMPOSITION WITH BACTERIAL ACTIVITY THAT INCLUDES IT
IS4351A IS4351A (en) 1995-06-06 1996-06-03 New crystalline form of 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, methanesulfonic acid salt and use and process thereof
LVP-96-172A LV11619B (en) 1995-06-06 1996-06-04 Novel crystal form of 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, methanesulfonic acid salt
UA96062190A UA44718C2 (en) 1995-06-06 1996-06-04 CRYSTAL FORM OF METHANSULPHONATE SALT 7 - ([1 <font face = "Symbol"> a </font>, 5 <font face = "Symbol"> a </font>, 6 <font face = "Symbol"> a </ font>] - 6-AMINO-3-AZABICYCLO [3.1.0] HEX-3-YL) -6-FLUORO-1- (2,4-DIFLUTORPHENYL) -1,4-DIHYDRO-4-OXO-1,8 -NAPHTHYRIDINE-3-CARBONIC ACID, METHOD OF ITS PRODUCTION, PHARMACEUTICAL COMPOSITION WITH ANTI-BACTERIAL ACTIVITY, TAPALOUS AND TAPASI
BR9602630A BR9602630A (en) 1995-06-06 1996-06-04 Acido7 - ([1alpha, 5alpha, 6alpha]) - 6-amino-3-azabicyclo [3.1.0.] Hex-3-yl) -6-fluor-1- (2,4-difluorophenyl) -1,4- dihydro-4-oxo-1,8-naphthyridine-3-carboxylic, pharmaceutical composition method of treating a bacterial infection and process for preparing the compound
PL96314604A PL314604A1 (en) 1995-06-06 1996-06-04 Novel crystalline form of anhydrous methasulphonic salt of 7-([1alpha,5alpha,6alpha]-6-amino-3-azabicyclo-{3.1.0]hex-3-ylo)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-keto-1,8-naphtytidino-3-carboxylic acid
BG100639A BG62443B1 (en) 1995-06-06 1996-06-05 3-Azabicyclo [3.1.0] -hex-3-yl) -6-fluoro-1- (2,4-difluorophenyl) -lH- , 4-DIHYDRO-4-OXO-1,8-NAPHYRIDINE-3-CARBOXYLIC ACID, METHANESULPHONIC ACID SALT
NO962321A NO305599B1 (en) 1995-06-06 1996-06-05 New Crystal Forms of Anhydrous 7 - ([1 <alpha>, 5 <alpha>, 6 <alpha>] -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 salt, process thereof and preparation
RU96111026A RU2125571C1 (en) 1995-06-06 1996-06-05 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-NAPHTHYRIDINE-3- -CARBOXYLIC AND METHANESULFONIC ACIDS SALT AND A METHOD OF ITS SYNTHESIS
SG1996009972A SG54339A1 (en) 1995-06-06 1996-06-05 Novel crystal form of anhydrous 7-(1alpha,salpha, 6alpha,]-6-amino-3-azabicyclo [3.1.0]hex-3-yl)-6-fluoro-1-(2,4-difluorophenyl) (pls refer to file for full detail)
HU9601540A HUP9601540A3 (en) 1995-06-06 1996-06-05 Novel crystal form of anhydrous 7-([1alpha, 5alpha, 6alpha]-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 salt
MA24262A MA23892A1 (en) 1995-06-06 1996-06-05 NEW CRYSTALLINE FORM OF METHANESULFONIC ACID SALT OF ACID 7- (1X, 5X, 6X) -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- CARBOXYLIC ANHYDROUS, PROCESS FOR ITS PREPARATION AND COMPOSITION CONTAINING IT
YU34596A YU34596A (en) 1995-06-06 1996-06-05 NEW CRYSTAL FORM OF ANHIDROVANE 7 - ([[1α, 5α, 6α] -6-AMINO-3-AZABICYCLO [3.1.0] HEKS-3-IL) -6-6FLUORO-1- (2,4-DIFLUOROPHENYL) -1. 4-DIHYDRO-4-OXO-1,8-NAFTRIDINE-3-CARBOXYLIC ACIDS, ARE METANSULFO ACIDS, ITS PHARMACEUTICAL MIXTURE AND PROCEDURE FOR ITS PREPARATION
KR1019960020171A KR100191989B1 (en) 1995-06-06 1996-06-05 Novel 7-((1alpha, 5alpha, 6alpha) -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 salt
CZ961625A CZ285878B6 (en) 1995-06-06 1996-06-05 Crystalline form of anhydrous salt of 7-([1alpha, 5alpha, 6alpha]-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 and methanesulfonic acid, process of its preparation and pharmaceutical compositions based thereon
TNTNSN96084A TNSN96084A1 (en) 1995-06-06 1996-06-05 NEW CRYSTALLINE FORM OF METHANESULFONIC ACID SALT OF ACID 7 - ([1 α, 5 α, 6 α] - 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 - CARBOXYLIC ANHYDROUS, PROCESS FOR ITS PREPARATION AND PHARMACEUTICAL COMPOSITION CONTAINING IT
AU54749/96A AU703634B2 (en) 1995-06-06 1996-06-05 Novel crystalline forms of anhydrous 7-{(1alpha,5alpha, 6alpha)-6-amino-3-azabicyclo(3.1.0)hex-3-y1}-6-fluoro-1- (2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3- carboxylic acid, methanesulfonic acid salt.
ZA9604647A ZA964647B (en) 1995-06-06 1996-06-05 Novel crystal form of anhydrous 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-carboxylic acid, methanesulfonic acid salt.
NZ286735A NZ286735A (en) 1995-06-06 1996-06-05 Crystal form of a 7-(azabicyclohexyl)-naphthyridine-3-carboxylic acid salt; medicaments
DZ960090A DZ2046A1 (en) 1995-06-06 1996-06-05 New crystalline form of the methanesulfonic acid salt of 7-Ä (1alpha, 5alpha, 6alphaÜ-6-amino-3-azabicycloÄ3.1.0Ühex-3-yl) -6-fluoro -1- (2,4-difluorophenyl ) -1,4 dihydro-4-oxo-1,8-naphthyridine-3-anhydrous carboxylic acid, process for its preparation and pharmaceutical composition containing it.
HR960267A HRP960267B1 (en) 1995-06-06 1996-06-06 Novel crystal form of anhydrous 7-(/1'alpha, 5'alpha, 6'alpha/-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 salt
SI9600185A SI9600185A (en) 1995-06-06 1996-06-06 Novel crystal form of anhydrous 7-((1alpha, 5alpha,6alpha)-6-amino-3-azabicyclo (3.1.0.) hex-3-il) -6-fluoro-1- (2,4 difluorophenyl) -1,4-dihydro-4-oxo-1,8 naphthyridine -3-carboxylic acids, methanesulfonic acid salt
PE1996000421A PE38097A1 (en) 1995-06-06 1996-06-06 NEW CRYSTALLINE FORM OF ACID 7 - ([1a, 5a, 6a] -6-AMINO-3-AZABICICLO [3.1.0] HEX-3-IL) -6-FLUOR-1- (2,4-DIFLUOROFENIL) -1 , 4-DIHIDRO-4-OXO-1,8-NAFTIRIDIN-3-CARBOXILICO ANHYDRO, SALT OF METHANOSULPHONIC ACID
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
UY25459A UY25459A1 (en) 1995-06-06 1999-04-06 PROCEDURE FOR PREPARING A CRYSTALLINE FORM OF ACID 7 - ([1A, 5A, 6A] -6-AMINO-3-AZABICYCLO [3, 1, 0] HEX-3-IL) -6-FL UOR-1- (2, 4-DIFLUOROPHENYL) -1, 4-DIHYDRO-4-OXO-1, 8-NAFTIRIDIN -3-CARBOXYL ANHYDRO, SALT OF METHANOSULPHONIC ACID

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WO1999035143A1 (en) * 1998-01-06 1999-07-15 Knoll Aktiengesellschaft Method for producing doxazodin mesylate in a crystal modification designated as form a and intermediate product for producing the same
EP0982031A3 (en) * 1998-08-21 2000-03-08 Pfizer Inc. Antifungal compositions comprising voriconazole and trovafloxacin or prodrugs thereof
WO2000017199A1 (en) * 1998-09-18 2000-03-30 Smithkline Beecham P.L.C. Process for the production of a naphthyridine carboxylic acid derivative (methanesulfonate sesquihydrate)
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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
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
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
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
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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
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Cited By (17)

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US7700617B2 (en) 1997-03-21 2010-04-20 Lg Life Sciences, Ltd. Salt of naphthyridine carboxylic acid derivative
US6723734B2 (en) 1997-03-21 2004-04-20 Lg Life Sciences, Ltd. Salt of naphthyridine carboxylic acid derivative
US6194429B1 (en) 1997-08-01 2001-02-27 Pfizer Inc Alatrofloxacin parenteral compositions
US6500830B1 (en) 1998-01-06 2002-12-31 Knoll Aktiengesellschaft Conversion of modification D to modification A of doxazosin mesylate
WO1999035143A1 (en) * 1998-01-06 1999-07-15 Knoll Aktiengesellschaft Method for producing doxazodin mesylate in a crystal modification designated as form a and intermediate product for producing the same
EP0982031A3 (en) * 1998-08-21 2000-03-08 Pfizer Inc. Antifungal compositions comprising voriconazole and trovafloxacin or prodrugs thereof
US6818771B1 (en) 1998-09-18 2004-11-16 Lg Life Sciences Limited Process for the production of a naphthyridine carboxylic acid derivative (methanesulfonate sesquihydrate)
KR100679062B1 (en) * 1998-09-18 2007-02-05 주식회사 엘지생명과학 Manufacturing method of naphthyridine carboxylic acid derivative (methanesulfonate sesquihydrate)
WO2000017199A1 (en) * 1998-09-18 2000-03-30 Smithkline Beecham P.L.C. Process for the production of a naphthyridine carboxylic acid derivative (methanesulfonate sesquihydrate)
ES2164520A1 (en) * 1999-03-16 2002-02-16 Medichem Sa Method for obtaining polymorph a from doxazosine mesylate
US6525195B1 (en) 1999-03-16 2003-02-25 Medichem, S.A. Method for obtaining polymorph a from doxazosine mesylate
WO2000055157A1 (en) * 1999-03-16 2000-09-21 Medichem S.A. Method for obtaining polymorph a from doxazosine mesylate
US6239141B1 (en) 1999-06-04 2001-05-29 Pfizer Inc. Trovafloxacin oral suspensions
US6703512B1 (en) 1999-09-03 2004-03-09 Sb Pharmco Puerto Rico Inc. Of The United States Corporation Company Intermediates for the production of quinolone carboxylic acid derivatives
US6803467B2 (en) 1999-09-03 2004-10-12 Lg Life Sciences Limited Intermediates for the production of quinolone carboxylic acid derivatives
US7232907B2 (en) 1999-09-03 2007-06-19 Lg Life Sciences Limited Process for production of naphthyridine-3-carboxylic acid derivatives
US7361762B2 (en) 2002-04-08 2008-04-22 Lg Life Sciences Ltd. Process for preparing acid salts of Gemifloxacin

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