EP1159277A1 - Modification cristalline d de l'acide 8-cyano-1- cyclopropyl -7- (1s, 6s- 2,8- diazabicyclo - 4.3.0] nonan-8-yl) -6-fluoro -1,4- dihydro -4-oxo -3-quinoleine -carboxylique - Google Patents
Modification cristalline d de l'acide 8-cyano-1- cyclopropyl -7- (1s, 6s- 2,8- diazabicyclo - 4.3.0] nonan-8-yl) -6-fluoro -1,4- dihydro -4-oxo -3-quinoleine -carboxyliqueInfo
- Publication number
- EP1159277A1 EP1159277A1 EP00909167A EP00909167A EP1159277A1 EP 1159277 A1 EP1159277 A1 EP 1159277A1 EP 00909167 A EP00909167 A EP 00909167A EP 00909167 A EP00909167 A EP 00909167A EP 1159277 A1 EP1159277 A1 EP 1159277A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- ccdc
- modification
- diazabicyclo
- cyclopropyl
- dihydro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000012986 modification Methods 0.000 title claims abstract description 38
- 230000004048 modification Effects 0.000 title claims abstract description 38
- 239000013078 crystal Substances 0.000 title claims abstract description 22
- -1 nonan-8-yl Chemical group 0.000 title claims description 8
- 239000000843 powder Substances 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 4
- IGRCWJPBLWGNPX-UHFFFAOYSA-N 3-(2-chlorophenyl)-n-(4-chlorophenyl)-n,5-dimethyl-1,2-oxazole-4-carboxamide Chemical compound C=1C=C(Cl)C=CC=1N(C)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl IGRCWJPBLWGNPX-UHFFFAOYSA-N 0.000 claims description 32
- 239000007787 solid Substances 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- 238000002844 melting Methods 0.000 claims description 3
- 230000008018 melting Effects 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 230000011514 reflex Effects 0.000 claims description 3
- 230000007704 transition Effects 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 2
- 239000003242 anti bacterial agent Substances 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 238000004455 differential thermal analysis Methods 0.000 description 5
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- KSCPLKVBWDOSAI-NKWVEPMBSA-N (4as,7as)-2,3,4,4a,5,6,7,7a-octahydro-1h-pyrrolo[3,4-b]pyridine Chemical compound N1CCC[C@H]2CNC[C@H]21 KSCPLKVBWDOSAI-NKWVEPMBSA-N 0.000 description 1
- PXTYIFUOEXJZEN-UHFFFAOYSA-N 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C12=C(C#N)C(Cl)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 PXTYIFUOEXJZEN-UHFFFAOYSA-N 0.000 description 1
- 101001080808 Homo sapiens PH and SEC7 domain-containing protein 2 Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 102100027455 PH and SEC7 domain-containing protein 2 Human genes 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- 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 present invention relates to a defined crystal modification of 8-cyano-1-cyclopropyl-7- (IS, 6S-2,8-diazabicyclo [4.3.0] nonan-8-yl) -6-fluoro-1,4-dihydro- 4-oxo-3-quinoline carboxylic acid, process for its preparation and its use in pharmaceutical preparations.
- CCDC is known from DE-A 19 633 805 or PCT application no. 97 903 260.4. It is then prepared by reacting 7-chloro-8-cyano-l-cyclopropyl-6-fluoro-l, 4-dihydro-4-oxo-3-quinolinecarboxylic acid with (lS, 6S) -2,8-diazabicyclo [4.3 .0] nonane in a mixture of dimethylformamide and acetonitrile in the presence of an auxiliary base. After adding water, CCDC is extracted from water with dichloromethane and isolated by removing the extractant. You get one
- the partly Amorphous powder obtained by the manufacturing process outlined above is also hygroscopic. Amorphous solids, and even more hygroscopic
- Solids are difficult to handle in galenical processing because they have low bulk densities and poor flow properties, for example.
- special working techniques and facilities are required to handle hygroscopic solids in order to achieve reproducible results, e.g. with regard to the active substance content or stability in the solid formulations produced.
- the invention is therefore based on the object of producing a crystalline form of defined modification of CCDC which, owing to its physical properties, in particular its crystal properties, is easy to handle in pharmaceutical formulations.
- the invention therefore relates to the crystalline modification D of CCDC, which is characterized in that it has an X-ray powder diffractogram with the reflex positions (2 theta) of high and medium intensity (> 30% relative intensity) given in Table 1 below.
- Table 1 :
- Modification D according to the invention of CCDC also differs from other forms of CCDC in a number of other properties. This too
- CCDC of modification D is characterized in that it has a melting point of 261 ° C. to 265 ° C., determined with the aid of differential thermal analysis (DTA) Has.
- DTA differential thermal analysis
- CCDC of modification D is characterized in that it has an infrared spectrum measured in KBr as shown in Figure 3.
- the crystal modification D of CCDC is obtained by dissolving CCDC of unknown modification or amorphous CCDC in a concentration between 1 and 3 percent by weight in water, allowing this solution to stand until a solid precipitates, filtering off this solid, drying the water-containing product thus obtained and then heated to a temperature above the transition temperature.
- the water-containing product can be dried using standard methods.
- the water-containing product can be dried in a vacuum at an elevated temperature. It is also possible to carry out the drying in the presence of a customary drying agent such as, for example, phosphorus pentoxide.
- the temperature required to convert the dried sample into modification D can be determined by means of a DTA of the dried substance. As a rule, it is between 130 ° C and 160 ° C.
- CCDC of crystal modification D is surprisingly stable and does not convert into another crystal modification or the amorphous form even after prolonged storage. For these reasons, it is ideally suited for the production of tablets or other solid formulations. Its stability gives these formulations the desired long-term storage stability. With the crystal modification D, stable and solid preparations of CCDC can be produced in a targeted manner. CCDC of crystal modification D is extremely effective against pathogenic bacteria in the field of human or veterinary medicine. Its broad area of application corresponds to that of CCDC.
- D from CCDC was obtained with a transmission diffractometer STADI-P with location-sensitive detector (PSD2) from Stoe.
- the melting point of the differential thermal analysis was obtained with the device DSC 820 from Mettler-Toledo.
- the sample of CCDC of crystal modification D was heated in air in an aluminum crucible at 5 K / min.
- the IR spectrum was obtained in KBr using the 881 device from Perkin-Elmer.
- Aetonitrile is stirred for 16 hours at room temperature.
- the reaction mixture is concentrated on a rotary evaporator at a bath temperature of 60 ° C. and the residue is taken up in 10 ml of water.
- the resulting solution is adjusted to pH 7 with dilute hydrochloric acid and the solid is filtered off.
- the filtrate is extracted three times with 20 ml dichloromethane.
- the organic phase is dried over
- 1,012 g of 7-chloro-8-cyan-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarbonic acid are mixed in a mixture of 3,300 ml of ethanol and 1,980 ml of N-methyl -pyrroli- don and 534 g of Hünig base. The mixture is heated under reflux and then dripped
- the solid obtained is in a mixture of 4,650 ml of ethanol and 41 g
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- 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)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
L'invention concerne une modification cristalline définie de l'acide 8-cyano -1- cyclopropyl- 7- (1S, 6S-2,8- diazabicyclo [4.3.0] nonan -8-yl) -6-fluoro- 1,4- dihydro -4-oxo-3- quinoléine- carboxylique, des procédés de production de ce composé, ainsi que l'utilisation de ce dernier dans des préparations pharmaceutiques. Cette modification cristalline se distingue des autres modifications cristalline de l'acide 8-cyano -1-cyclopropyl -7- (1S, 6S-2,8-diazabicyclo [4.3.0] nonan - 8-yl) -6-fluoro -1,4-dihydro -4-oxo -3- quinoléine -carboxylique de formule (I), par son diffractogramme de rayons X sur poudre, caractéristique, et par son diagramme thermique différentiel.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19908448 | 1999-02-26 | ||
| DE19908448A DE19908448A1 (de) | 1999-02-26 | 1999-02-26 | Kristallmodifikation D von 8-Cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicylo[4.3.0)nonan-8-yl)-6-fluor-1,4-dihydro-4-oxo-3-chino incarbonsäure |
| PCT/EP2000/001203 WO2000052010A1 (fr) | 1999-02-26 | 2000-02-14 | Modification cristalline d de l'acide 8-cyano-1- cyclopropyl -7- (1s, 6s- 2,8- diazabicyclo -[4.3.0] nonan-8-yl) -6-fluoro -1,4- dihydro -4-oxo -3-quinoleine -carboxylique |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1159277A1 true EP1159277A1 (fr) | 2001-12-05 |
Family
ID=7899026
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP00909167A Withdrawn EP1159277A1 (fr) | 1999-02-26 | 2000-02-14 | Modification cristalline d de l'acide 8-cyano-1- cyclopropyl -7- (1s, 6s- 2,8- diazabicyclo - 4.3.0] nonan-8-yl) -6-fluoro -1,4- dihydro -4-oxo -3-quinoleine -carboxylique |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US6492391B1 (fr) |
| EP (1) | EP1159277A1 (fr) |
| JP (1) | JP2002538159A (fr) |
| KR (1) | KR100756474B1 (fr) |
| CN (1) | CN1217944C (fr) |
| AU (1) | AU760710B2 (fr) |
| BR (1) | BR0008520A (fr) |
| CA (1) | CA2362804A1 (fr) |
| CZ (1) | CZ20013065A3 (fr) |
| DE (1) | DE19908448A1 (fr) |
| HK (1) | HK1045158B (fr) |
| HU (1) | HUP0200053A3 (fr) |
| IL (1) | IL144528A0 (fr) |
| NO (1) | NO320314B1 (fr) |
| NZ (1) | NZ513749A (fr) |
| PL (1) | PL349394A1 (fr) |
| RU (1) | RU2248357C2 (fr) |
| SK (1) | SK11942001A3 (fr) |
| TR (1) | TR200102435T2 (fr) |
| UA (1) | UA71606C2 (fr) |
| WO (1) | WO2000052010A1 (fr) |
| ZA (1) | ZA200106050B (fr) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19854356A1 (de) | 1998-11-25 | 2000-05-31 | Bayer Ag | Kristallmodifikation A von 8-Cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-/4.3.0/nonan-8-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure |
| DE19854355A1 (de) | 1998-11-25 | 2000-05-31 | Bayer Ag | Kristallmodifikation B von 8-Cyan-1-cyclopropyl-7-(1S, 6S-2,8-diazabicyclo-/4.3.O/nonan-8-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure |
| DE19908449A1 (de) | 1999-02-26 | 2000-08-31 | Bayer Ag | Kristallmodifikation C von 8-Cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicylo-[4.3.0]nonan-8-yl)-6-fluor-1,4-dihydro-4-oxo-3-chino/incarbonsäure |
| DE102004015981A1 (de) | 2004-04-01 | 2005-10-20 | Bayer Healthcare Ag | Neue kirstalline Form von 8-Cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure |
| SG11201907073TA (en) | 2017-02-13 | 2019-08-27 | Bayer Animal Health Gmbh | Liquid composition containing pradofloxacin |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2676521B2 (ja) | 1988-03-22 | 1997-11-17 | 北陸製薬株式会社 | キノロンカルボン酸化合物ｉ型結晶の製造法 |
| WO1996016055A1 (fr) * | 1994-11-18 | 1996-05-30 | Pharmacia & Upjohn Company | Nouvelle forme physiquement stable d'une fluoroquinolone |
| ATE228130T1 (de) * | 1996-02-23 | 2002-12-15 | Bayer Ag | Gegebenenfalls substituierte 8-cyan-1-cyclopropyl-7-(2,8-diazabicyclo- 4.3.0)-nonan-8-yl)-6-fluor-1,4-dihydro-4-oxo-3- hinolincarbonsäuren und ihre derivate |
| DE19854356A1 (de) | 1998-11-25 | 2000-05-31 | Bayer Ag | Kristallmodifikation A von 8-Cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-/4.3.0/nonan-8-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure |
| DE19854355A1 (de) | 1998-11-25 | 2000-05-31 | Bayer Ag | Kristallmodifikation B von 8-Cyan-1-cyclopropyl-7-(1S, 6S-2,8-diazabicyclo-/4.3.O/nonan-8-yl)-6-fluor-1,4-dihydro-4-oxo-3-chinolincarbonsäure |
| DE19908449A1 (de) | 1999-02-26 | 2000-08-31 | Bayer Ag | Kristallmodifikation C von 8-Cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicylo-[4.3.0]nonan-8-yl)-6-fluor-1,4-dihydro-4-oxo-3-chino/incarbonsäure |
| JP2001242582A (ja) * | 2000-02-25 | 2001-09-07 | Fuji Photo Film Co Ltd | ハロゲン化銀写真感光材料およびその現像処理方法 |
-
1999
- 1999-02-26 DE DE19908448A patent/DE19908448A1/de not_active Withdrawn
-
2000
- 2000-02-14 US US09/914,031 patent/US6492391B1/en not_active Expired - Fee Related
- 2000-02-14 CZ CZ20013065A patent/CZ20013065A3/cs unknown
- 2000-02-14 KR KR1020017009632A patent/KR100756474B1/ko not_active Expired - Fee Related
- 2000-02-14 BR BR0008520-0A patent/BR0008520A/pt not_active IP Right Cessation
- 2000-02-14 NZ NZ513749A patent/NZ513749A/en unknown
- 2000-02-14 SK SK1194-2001A patent/SK11942001A3/sk not_active Application Discontinuation
- 2000-02-14 UA UA2001096577A patent/UA71606C2/uk unknown
- 2000-02-14 CN CN00804306XA patent/CN1217944C/zh not_active Expired - Fee Related
- 2000-02-14 HK HK02106690.8A patent/HK1045158B/zh not_active IP Right Cessation
- 2000-02-14 EP EP00909167A patent/EP1159277A1/fr not_active Withdrawn
- 2000-02-14 RU RU2001126301/04A patent/RU2248357C2/ru not_active IP Right Cessation
- 2000-02-14 WO PCT/EP2000/001203 patent/WO2000052010A1/fr not_active Ceased
- 2000-02-14 CA CA002362804A patent/CA2362804A1/fr not_active Abandoned
- 2000-02-14 JP JP2000602236A patent/JP2002538159A/ja not_active Withdrawn
- 2000-02-14 PL PL00349394A patent/PL349394A1/xx not_active Application Discontinuation
- 2000-02-14 AU AU31544/00A patent/AU760710B2/en not_active Ceased
- 2000-02-14 TR TR2001/02435T patent/TR200102435T2/xx unknown
- 2000-02-14 IL IL14452800A patent/IL144528A0/xx not_active IP Right Cessation
- 2000-02-14 HU HU0200053A patent/HUP0200053A3/hu unknown
-
2001
- 2001-07-24 ZA ZA200106050A patent/ZA200106050B/en unknown
- 2001-08-21 NO NO20014059A patent/NO320314B1/no unknown
Non-Patent Citations (1)
| Title |
|---|
| See references of WO0052010A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| DE19908448A1 (de) | 2000-08-31 |
| CA2362804A1 (fr) | 2000-09-08 |
| PL349394A1 (en) | 2002-07-15 |
| CN1217944C (zh) | 2005-09-07 |
| SK11942001A3 (sk) | 2001-12-03 |
| RU2248357C2 (ru) | 2005-03-20 |
| CZ20013065A3 (cs) | 2002-01-16 |
| HUP0200053A3 (en) | 2003-01-28 |
| UA71606C2 (uk) | 2004-12-15 |
| AU3154400A (en) | 2000-09-21 |
| BR0008520A (pt) | 2001-12-18 |
| US6492391B1 (en) | 2002-12-10 |
| AU760710B2 (en) | 2003-05-22 |
| KR100756474B1 (ko) | 2007-09-07 |
| HK1045158A1 (en) | 2002-11-15 |
| NO320314B1 (no) | 2005-11-21 |
| HUP0200053A2 (hu) | 2002-05-29 |
| IL144528A0 (en) | 2002-05-23 |
| WO2000052010A1 (fr) | 2000-09-08 |
| TR200102435T2 (tr) | 2002-01-21 |
| NO20014059D0 (no) | 2001-08-21 |
| HK1045158B (zh) | 2006-04-21 |
| NZ513749A (en) | 2003-10-31 |
| ZA200106050B (en) | 2002-07-24 |
| NO20014059L (no) | 2001-08-21 |
| CN1341116A (zh) | 2002-03-20 |
| KR20010093300A (ko) | 2001-10-27 |
| JP2002538159A (ja) | 2002-11-12 |
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