RU2002124134A - Способ синтеза промежуточного соединения для получения эктеинасцидина и фталасцидина - Google Patents
Способ синтеза промежуточного соединения для получения эктеинасцидина и фталасцидинаInfo
- Publication number
- RU2002124134A RU2002124134A RU2002124134/04A RU2002124134A RU2002124134A RU 2002124134 A RU2002124134 A RU 2002124134A RU 2002124134/04 A RU2002124134/04 A RU 2002124134/04A RU 2002124134 A RU2002124134 A RU 2002124134A RU 2002124134 A RU2002124134 A RU 2002124134A
- Authority
- RU
- Russia
- Prior art keywords
- compound
- give
- group
- cyclic
- synthesis
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract 6
- 150000001875 compounds Chemical class 0.000 title claims 10
- 230000015572 biosynthetic process Effects 0.000 title abstract 3
- 238000003786 synthesis reaction Methods 0.000 title abstract 3
- 238000004519 manufacturing process Methods 0.000 title 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims 3
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims 3
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims 3
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims 3
- 229940126657 Compound 17 Drugs 0.000 claims 3
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 claims 3
- 229940125773 compound 10 Drugs 0.000 claims 3
- 229940126543 compound 14 Drugs 0.000 claims 3
- 229940125758 compound 15 Drugs 0.000 claims 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- 238000003776 cleavage reaction Methods 0.000 claims 2
- 229940125797 compound 12 Drugs 0.000 claims 2
- 229940126142 compound 16 Drugs 0.000 claims 2
- 229940125898 compound 5 Drugs 0.000 claims 2
- 238000005828 desilylation reaction Methods 0.000 claims 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- 238000007069 methylation reaction Methods 0.000 claims 2
- -1 mono tert-butyldimethylsilyl Chemical group 0.000 claims 2
- 230000007017 scission Effects 0.000 claims 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 1
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 claims 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims 1
- 230000021736 acetylation Effects 0.000 claims 1
- 238000006640 acetylation reaction Methods 0.000 claims 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 229940125782 compound 2 Drugs 0.000 claims 1
- 238000006266 etherification reaction Methods 0.000 claims 1
- 230000003993 interaction Effects 0.000 claims 1
- 150000003951 lactams Chemical group 0.000 claims 1
- 150000002596 lactones Chemical class 0.000 claims 1
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical compound COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 claims 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims 1
- 150000003138 primary alcohols Chemical class 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 claims 1
- 150000003335 secondary amines Chemical class 0.000 claims 1
- 239000007858 starting material Substances 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims 1
- PKVRCIRHQMSYJX-AIFWHQITSA-N trabectedin Chemical compound C([C@@]1(C(OC2)=O)NCCC3=C1C=C(C(=C3)O)OC)S[C@@H]1C3=C(OC(C)=O)C(C)=C4OCOC4=C3[C@H]2N2[C@@H](O)[C@H](CC=3C4=C(O)C(OC)=C(C)C=3)N(C)[C@H]4[C@@H]21 PKVRCIRHQMSYJX-AIFWHQITSA-N 0.000 abstract 2
- XXPXYPLPSDPERN-UHFFFAOYSA-N Ecteinascidin 743 Natural products COc1cc2C(NCCc2cc1O)C(=O)OCC3N4C(O)C5Cc6cc(C)c(OC)c(O)c6C(C4C(S)c7c(OC(=O)C)c(C)c8OCOc8c37)N5C XXPXYPLPSDPERN-UHFFFAOYSA-N 0.000 abstract 1
- 239000002246 antineoplastic agent Substances 0.000 abstract 1
- 230000003389 potentiating effect Effects 0.000 abstract 1
- 229960000977 trabectedin Drugs 0.000 abstract 1
- 0 CC(CC1[C@](C#N)N([C@]2C*)[C@]3Cc(c(O)c4C)c2c2c4OCO2)(c2cc(*)c4OC)N1C3c2c4OCOC Chemical compound CC(CC1[C@](C#N)N([C@]2C*)[C@]3Cc(c(O)c4C)c2c2c4OCO2)(c2cc(*)c4OC)N1C3c2c4OCOC 0.000 description 2
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Claims (5)
1. Способ получения фталасцидина, соединения 2:
включающий стадии:
(а) преобразования соединения 11:
в моно трет-бутилдиметилсилиловый (ТБС) эфир, соединения 12:
(b) этерификации с помощью метоксиметилхлорида с получением соединения 13:
(с) отщепления N-аллилоксикарбонильной и O-аллильной групп у соединения 13 с получением вторичного амина, соединения 14:
(d) N-метилирования соединения 14 с получением соединения 15:
(е) С-метилирования соединения 15 с получением соединения 16:
(f) ацетилирования фенола 16 с получением соответствующего ацетата, соединения 17:
(g) десилилирования соединения 17, с получением первичного спирта, соединения 18:
(h) замещения по Мицунобу первичного гидроксила соединения 18 с получением фталимида, соединения 19:
и
(i) кислотно-катализируемого отщепления метоксиметилового эфира у соединения 19.
2. Способ по п.1, где исходное соединение 11 получено путем введения гидроксизащитной группы в пятициклический аминонитрил, соединение 5:
3. Способ по п.2, где пятициклический аминонитрил, соединение 5, получен способом, включающим стадии:
(а) взаимодействия соединения 3b:
с аминолактоном 4:
в присутствии ацилирующего агента с получением продукта присоединения 6:
(b) обработки соединения 6 аллилбромидом с получением амида 7:
(с) восстановления лактона 7 до соответствующего лактола 8:
(d) десилилирования соединения 8 с получением соединения 9:
(е) циклизации соединения 9 с получением соединения 10:
и
(f) восстановления лактамной группы в соединении 10 до соответствующего циклического аминаля и обработки HCN.
4. Соединение, выбранное из группы, включающей соединение 6:
соединение 7:
соединение 8:
соединение 9:
и соединение 10:
5. Соединение, выбранное из группы, включающей соединение 11:
соединение 12:
соединение 13:
соединение 14:
соединение 15:
соединение 16:
соединение 17:
соединение 18:
и соединение 19:
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US18179500P | 2000-02-11 | 2000-02-11 | |
| US60/181,795 | 2000-02-11 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| RU2002124134A true RU2002124134A (ru) | 2004-01-10 |
| RU2267492C2 RU2267492C2 (ru) | 2006-01-10 |
Family
ID=22665840
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| RU2002124134/04A RU2267492C2 (ru) | 2000-02-11 | 2001-02-09 | Способ синтеза фталасцидина и промежуточных продуктов и промежуточные соединения |
Country Status (22)
| Country | Link |
|---|---|
| EP (1) | EP1255759B1 (ru) |
| JP (1) | JP5102925B2 (ru) |
| KR (1) | KR100768331B1 (ru) |
| CN (1) | CN1230437C (ru) |
| AT (1) | ATE368670T1 (ru) |
| AU (2) | AU3813501A (ru) |
| BR (1) | BRPI0108279B1 (ru) |
| CA (1) | CA2400614C (ru) |
| CY (1) | CY1107769T1 (ru) |
| CZ (1) | CZ300326B6 (ru) |
| DE (1) | DE60129669T2 (ru) |
| DK (1) | DK1255759T3 (ru) |
| ES (1) | ES2290114T3 (ru) |
| HU (1) | HU229511B1 (ru) |
| IL (2) | IL151168A0 (ru) |
| MX (1) | MXPA02007767A (ru) |
| NO (1) | NO328648B1 (ru) |
| NZ (1) | NZ520635A (ru) |
| PL (1) | PL209762B1 (ru) |
| PT (1) | PT1255759E (ru) |
| RU (1) | RU2267492C2 (ru) |
| WO (1) | WO2001058905A1 (ru) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP6037337B2 (ja) | 2010-05-25 | 2016-12-07 | ファルマ、マール、ソシエダード、アノニマＰｈａｒｍａ Ｍｒｓ，Ｓ．Ａ． | エクチナサイジン化合物の製造のための合成方法 |
| CN108101934B (zh) * | 2016-11-24 | 2022-02-08 | 江苏恒瑞医药股份有限公司 | 用于制备曲贝替定的方法及其中间体 |
| CN110092802B (zh) * | 2019-06-21 | 2022-01-07 | 爱斯特（成都）生物制药股份有限公司 | 一种制备曲贝替定中间体的方法 |
| CN112745327B (zh) * | 2019-10-30 | 2023-08-25 | 南通诺泰生物医药技术有限公司 | 一种曲贝替定中间体化合物的制备方法 |
| CN114621245A (zh) * | 2020-12-11 | 2022-06-14 | 江苏恒瑞医药股份有限公司 | 一种曲贝替定中间体的晶型及其制备方法 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5721362A (en) * | 1996-09-18 | 1998-02-24 | President And Fellows Of Harvard College | Process for producing ecteinascidin compounds |
| US6124292A (en) * | 1998-09-30 | 2000-09-26 | President And Fellows Of Harvard College | Synthetic analogs of ecteinascidin-743 |
-
2001
- 2001-02-09 KR KR1020027010342A patent/KR100768331B1/ko active IP Right Grant
- 2001-02-09 HU HU0204221A patent/HU229511B1/hu unknown
- 2001-02-09 NZ NZ520635A patent/NZ520635A/en not_active IP Right Cessation
- 2001-02-09 ES ES01910540T patent/ES2290114T3/es not_active Expired - Lifetime
- 2001-02-09 PT PT01910540T patent/PT1255759E/pt unknown
- 2001-02-09 AT AT01910540T patent/ATE368670T1/de active
- 2001-02-09 BR BRPI0108279A patent/BRPI0108279B1/pt active IP Right Grant
- 2001-02-09 CA CA2400614A patent/CA2400614C/en not_active Expired - Lifetime
- 2001-02-09 MX MXPA02007767A patent/MXPA02007767A/es active IP Right Grant
- 2001-02-09 DK DK01910540T patent/DK1255759T3/da active
- 2001-02-09 PL PL356392A patent/PL209762B1/pl unknown
- 2001-02-09 CZ CZ20022683A patent/CZ300326B6/cs not_active IP Right Cessation
- 2001-02-09 AU AU3813501A patent/AU3813501A/xx active Pending
- 2001-02-09 RU RU2002124134/04A patent/RU2267492C2/ru active
- 2001-02-09 JP JP2001558054A patent/JP5102925B2/ja not_active Expired - Lifetime
- 2001-02-09 DE DE60129669T patent/DE60129669T2/de not_active Expired - Lifetime
- 2001-02-09 WO PCT/US2001/004376 patent/WO2001058905A1/en active IP Right Grant
- 2001-02-09 IL IL15116801A patent/IL151168A0/xx unknown
- 2001-02-09 EP EP01910540A patent/EP1255759B1/en not_active Expired - Lifetime
- 2001-02-09 CN CNB018070973A patent/CN1230437C/zh not_active Expired - Lifetime
- 2001-02-09 AU AU2001238135A patent/AU2001238135B2/en not_active Expired
-
2002
- 2002-08-09 NO NO20023769A patent/NO328648B1/no not_active IP Right Cessation
- 2002-08-09 IL IL151168A patent/IL151168A/en active IP Right Grant
-
2007
- 2007-10-19 CY CY20071101347T patent/CY1107769T1/el unknown
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