DE60110043T2 - Methode zur synthetisierung von leflunomid - Google Patents
Methode zur synthetisierung von leflunomid Download PDFInfo
- Publication number
- DE60110043T2 DE60110043T2 DE60110043T DE60110043T DE60110043T2 DE 60110043 T2 DE60110043 T2 DE 60110043T2 DE 60110043 T DE60110043 T DE 60110043T DE 60110043 T DE60110043 T DE 60110043T DE 60110043 T2 DE60110043 T2 DE 60110043T2
- Authority
- DE
- Germany
- Prior art keywords
- methylisoxazole
- leflunomide
- carboxylic acid
- mia
- chloride
- 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.)
- Expired - Fee Related
Links
- 238000000034 method Methods 0.000 title claims abstract description 59
- 230000003407 synthetizing effect Effects 0.000 title 1
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 claims abstract description 72
- 229960000681 leflunomide Drugs 0.000 claims abstract description 71
- 230000008569 process Effects 0.000 claims abstract description 22
- ODGIMMLDVSWADK-UHFFFAOYSA-N 4-trifluoromethylaniline Chemical compound NC1=CC=C(C(F)(F)F)C=C1 ODGIMMLDVSWADK-UHFFFAOYSA-N 0.000 claims abstract description 13
- VQBXUKGMJCPBMF-UHFFFAOYSA-N 5-methyl-1,2-oxazole-4-carboxylic acid Chemical compound CC=1ON=CC=1C(O)=O VQBXUKGMJCPBMF-UHFFFAOYSA-N 0.000 claims abstract description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 45
- 239000002904 solvent Substances 0.000 claims description 36
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 24
- 238000005660 chlorination reaction Methods 0.000 claims description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 20
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- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229960005010 orotic acid Drugs 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
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- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
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- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229940087562 sodium acetate trihydrate Drugs 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
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- 229960002920 sorbitol Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
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- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
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- 239000000829 suppository Substances 0.000 description 1
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- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
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- 229910052623 talc Inorganic materials 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Pulmonology (AREA)
- Rheumatology (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Ophthalmology & Optometry (AREA)
- Pain & Pain Management (AREA)
- Transplantation (AREA)
- Otolaryngology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US18263500P | 2000-02-15 | 2000-02-15 | |
| US182635P | 2000-02-15 | ||
| PCT/US2001/004095 WO2001060363A1 (en) | 2000-02-15 | 2001-02-08 | A method for synthesizing leflunomide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE60110043D1 DE60110043D1 (de) | 2005-05-19 |
| DE60110043T2 true DE60110043T2 (de) | 2006-03-02 |
Family
ID=22669359
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE60110043T Expired - Fee Related DE60110043T2 (de) | 2000-02-15 | 2001-02-08 | Methode zur synthetisierung von leflunomid |
Country Status (18)
| Country | Link |
|---|---|
| US (2) | US6723855B2 (enExample) |
| EP (1) | EP1257270B1 (enExample) |
| JP (1) | JP2004500380A (enExample) |
| KR (1) | KR20020072312A (enExample) |
| AT (1) | ATE292966T1 (enExample) |
| AU (1) | AU2001234943A1 (enExample) |
| CA (1) | CA2400290A1 (enExample) |
| CZ (1) | CZ20023024A3 (enExample) |
| DE (1) | DE60110043T2 (enExample) |
| ES (1) | ES2237553T3 (enExample) |
| HR (1) | HRP20020671A2 (enExample) |
| HU (1) | HUP0301865A3 (enExample) |
| IL (1) | IL151196A0 (enExample) |
| PL (1) | PL366088A1 (enExample) |
| SK (1) | SK12992002A3 (enExample) |
| WO (1) | WO2001060363A1 (enExample) |
| YU (1) | YU61602A (enExample) |
| ZA (1) | ZA200206494B (enExample) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE207065T1 (de) * | 1997-08-08 | 2001-11-15 | Aventis Pharma Gmbh | Kristallform von n-(4-trifluormethylphenyl)-5- methylisoxazol-4-carbonsäureamid |
| HUP0204069A3 (en) * | 1999-12-16 | 2005-01-28 | Teva Pharma | Novel processes for making- and a new crystalline form of- leflunomide and pharmaceutical composition containing it |
| GB0123571D0 (en) * | 2001-04-05 | 2001-11-21 | Aventis Pharm Prod Inc | Use of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4'-trifluoromethylphenyl)-amide for treating multiple sclerosis |
| US20030139606A1 (en) * | 2001-11-09 | 2003-07-24 | Ray Anup Kumar | Process for preparing 5-methylisoxazole-4-carboxylic- (4'-trifluoromethyl)-anilide |
| RU2365373C2 (ru) * | 2003-05-27 | 2009-08-27 | Роберт Пер Хэгерквист | Применение ингибитора тирозинкиназы для лечения диабета |
| EP1694308A1 (en) * | 2003-10-30 | 2006-08-30 | Lupin Ltd. | Stable formulations of ace inhibitors and methods for preparation thereof |
| US20060024376A1 (en) * | 2004-07-30 | 2006-02-02 | The University Of Chicago | Methods and compositions for reducing toxicity associated with leflunomide treatment |
| DE102005017592A1 (de) * | 2005-04-16 | 2006-10-19 | Lindner, Jürgen, Dr. med. | Darreichungsformen und Kombinationspräparate von Pyrimidinbiosyntheseinhibitoren zur Erzielung zusätzlicher Wirkungen auf das Immunsystem |
| WO2007086076A2 (en) * | 2006-01-24 | 2007-08-02 | Unichem Laboratories Limited | An improved process for preparation of leflunomide |
| CN101817797B (zh) * | 2009-02-26 | 2013-04-10 | 江苏亚邦爱普森药业有限公司 | 高纯度3-甲基-n-[4-(三氟甲基)苯基]-4-异噁唑甲酰胺的合成方法 |
| CA2772275A1 (en) | 2009-09-18 | 2011-03-24 | Sanofi | (z)-2-cyano-3-hydroxy-but-2-enoic acid-(4'-trifluormethylphenyl)-amide tablet formulations with improved stability |
| CN102002009B (zh) * | 2010-10-18 | 2012-11-07 | 齐鲁制药有限公司 | 一种5-甲基异恶唑-4-甲酰氯的制备方法 |
| US10526279B2 (en) | 2015-06-17 | 2020-01-07 | Biocon Limited | Process for the preparation of teriflunomide |
| JOP20190207A1 (ar) * | 2017-03-14 | 2019-09-10 | Actelion Pharmaceuticals Ltd | تركيبة صيدلانية تشتمل على بونيسيمود |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2854439A1 (de) * | 1978-12-16 | 1980-07-03 | Hoechst Ag | Ein isoxazolderivat, verfahren zu seiner herstellung, diese verbindung enthaltende mittel und verwendung |
| GB8619432D0 (en) | 1986-08-08 | 1986-09-17 | Lilly Industries Ltd | Pharmaceutical compounds |
| AU649421B2 (en) * | 1990-05-18 | 1994-05-26 | Sanofi-Aventis Deutschland Gmbh | Isoxazole-4-carboxamides and hydroxyalkylidene-cyanoacetamides, drugs containing these compounds and use of such drugs |
| ES2124800T3 (es) | 1993-01-08 | 1999-02-16 | Hoechst Ag | Empleo de leflunomida para la inhibicion de interleuquina 1 beta. |
| US5610173A (en) | 1994-01-07 | 1997-03-11 | Sugen, Inc. | Formulations for lipophilic compounds |
| ATE207065T1 (de) * | 1997-08-08 | 2001-11-15 | Aventis Pharma Gmbh | Kristallform von n-(4-trifluormethylphenyl)-5- methylisoxazol-4-carbonsäureamid |
| DE19908527C2 (de) * | 1999-02-26 | 2001-08-30 | Aventis Pharma Gmbh | Verfahren zur Kristallisation von N-(4-Trifluormethylphenyl)-5-methyl-isoxazol-4-carboxamid |
| HUP0204069A3 (en) * | 1999-12-16 | 2005-01-28 | Teva Pharma | Novel processes for making- and a new crystalline form of- leflunomide and pharmaceutical composition containing it |
-
2001
- 2001-02-08 EP EP01907127A patent/EP1257270B1/en not_active Expired - Lifetime
- 2001-02-08 PL PL01366088A patent/PL366088A1/xx not_active Application Discontinuation
- 2001-02-08 US US09/779,928 patent/US6723855B2/en not_active Expired - Fee Related
- 2001-02-08 WO PCT/US2001/004095 patent/WO2001060363A1/en not_active Ceased
- 2001-02-08 KR KR1020027010595A patent/KR20020072312A/ko not_active Ceased
- 2001-02-08 AT AT01907127T patent/ATE292966T1/de not_active IP Right Cessation
- 2001-02-08 HU HU0301865A patent/HUP0301865A3/hu unknown
- 2001-02-08 HR HRP20020671 patent/HRP20020671A2/hr not_active Application Discontinuation
- 2001-02-08 JP JP2001559460A patent/JP2004500380A/ja active Pending
- 2001-02-08 AU AU2001234943A patent/AU2001234943A1/en not_active Abandoned
- 2001-02-08 ES ES01907127T patent/ES2237553T3/es not_active Expired - Lifetime
- 2001-02-08 YU YU61602A patent/YU61602A/sh unknown
- 2001-02-08 DE DE60110043T patent/DE60110043T2/de not_active Expired - Fee Related
- 2001-02-08 CZ CZ20023024A patent/CZ20023024A3/cs unknown
- 2001-02-08 IL IL15119601A patent/IL151196A0/xx unknown
- 2001-02-08 SK SK1299-2002A patent/SK12992002A3/sk unknown
- 2001-02-08 CA CA002400290A patent/CA2400290A1/en not_active Abandoned
-
2002
- 2002-08-14 ZA ZA200206494A patent/ZA200206494B/en unknown
-
2003
- 2003-12-10 US US10/730,949 patent/US20040127532A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| CZ20023024A3 (cs) | 2003-05-14 |
| WO2001060363A1 (en) | 2001-08-23 |
| AU2001234943A1 (en) | 2001-08-27 |
| IL151196A0 (en) | 2003-04-10 |
| YU61602A (sh) | 2006-01-16 |
| ES2237553T3 (es) | 2005-08-01 |
| PL366088A1 (en) | 2005-01-24 |
| DE60110043D1 (de) | 2005-05-19 |
| HRP20020671A2 (en) | 2004-12-31 |
| CA2400290A1 (en) | 2001-08-23 |
| KR20020072312A (ko) | 2002-09-14 |
| ZA200206494B (en) | 2003-08-20 |
| EP1257270A1 (en) | 2002-11-20 |
| SK12992002A3 (sk) | 2003-05-02 |
| EP1257270A4 (en) | 2003-05-07 |
| US6723855B2 (en) | 2004-04-20 |
| US20040127532A1 (en) | 2004-07-01 |
| HUP0301865A2 (hu) | 2003-09-29 |
| US20020022646A1 (en) | 2002-02-21 |
| JP2004500380A (ja) | 2004-01-08 |
| HUP0301865A3 (en) | 2005-12-28 |
| EP1257270B1 (en) | 2005-04-13 |
| ATE292966T1 (de) | 2005-04-15 |
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