CZ20032171A3 - 8-{4-[3-(5-fluor-1H-indol-3-yl)propyl]piperazin-1-yl}-2-methyl-4H-benzo[1,4]oxazin-3-on-mesylát s vysokou afinitou vůči dopaminovému D2 receptoru a místu reabsorpce serotoninu a farmaceutický prostředek s jeho obsahem - Google Patents
8-{4-[3-(5-fluor-1H-indol-3-yl)propyl]piperazin-1-yl}-2-methyl-4H-benzo[1,4]oxazin-3-on-mesylát s vysokou afinitou vůči dopaminovému D2 receptoru a místu reabsorpce serotoninu a farmaceutický prostředek s jeho obsahem Download PDFInfo
- Publication number
- CZ20032171A3 CZ20032171A3 CZ20032171A CZ20032171A CZ20032171A3 CZ 20032171 A3 CZ20032171 A3 CZ 20032171A3 CZ 20032171 A CZ20032171 A CZ 20032171A CZ 20032171 A CZ20032171 A CZ 20032171A CZ 20032171 A3 CZ20032171 A3 CZ 20032171A3
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- Prior art keywords
- mesylate
- dopamine
- oxazin
- piperazin
- indol
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- DSARBXFENDRZNI-UHFFFAOYSA-N 8-[4-[3-(5-fluoro-1h-indol-3-yl)propyl]piperazin-1-yl]-2-methyl-4h-1,4-benzoxazin-3-one;methanesulfonic acid Chemical compound CS(O)(=O)=O.C1=C(F)C=C2C(CCCN3CCN(CC3)C3=CC=CC4=C3OC(C(N4)=O)C)=CNC2=C1 DSARBXFENDRZNI-UHFFFAOYSA-N 0.000 title claims 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 title description 4
- 230000009103 reabsorption Effects 0.000 title description 2
- 229940076279 serotonin Drugs 0.000 title description 2
- 102000004980 Dopamine D2 Receptors Human genes 0.000 title 1
- 108090001111 Dopamine D2 Receptors Proteins 0.000 title 1
- 230000001747 exhibiting effect Effects 0.000 title 1
- 239000000825 pharmaceutical preparation Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 208000015114 central nervous system disease Diseases 0.000 claims 1
- 210000000653 nervous system Anatomy 0.000 claims 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 abstract description 6
- 239000012458 free base Substances 0.000 abstract description 6
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical class C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 abstract description 3
- 230000002349 favourable effect Effects 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 6
- 229960003638 dopamine Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 2
- 208000020114 Schizophrenia and other psychotic disease Diseases 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 239000000164 antipsychotic agent Substances 0.000 description 2
- 239000002249 anxiolytic agent Substances 0.000 description 2
- 230000000949 anxiolytic effect Effects 0.000 description 2
- 229940005530 anxiolytics Drugs 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- LDCYZAJDBXYCGN-VIFPVBQESA-N 5-hydroxy-L-tryptophan Chemical compound C1=C(O)C=C2C(C[C@H](N)C(O)=O)=CNC2=C1 LDCYZAJDBXYCGN-VIFPVBQESA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010003805 Autism Diseases 0.000 description 1
- 208000020706 Autistic disease Diseases 0.000 description 1
- 208000009132 Catalepsy Diseases 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 208000012886 Vertigo Diseases 0.000 description 1
- 206010047853 Waxy flexibility Diseases 0.000 description 1
- 230000016571 aggressive behavior Effects 0.000 description 1
- 229940005529 antipsychotics Drugs 0.000 description 1
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 1
- 229960004046 apomorphine Drugs 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000009194 climbing Effects 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- -1 mesylate compound Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000697 serotonin reuptake Effects 0.000 description 1
- 239000003772 serotonin uptake inhibitor Substances 0.000 description 1
- 230000002295 serotoninergic effect Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 231100000889 vertigo Toxicity 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- 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
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Psychiatry (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Virology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
Předkládaný vynález derivátu vzorce I se týká nového fenylpiperazinového
Dosavadní stav techniky
Patentová přihláška č. PCT/EP00/08090 (doposud nepublikovaná) se týká skupiny nových fenylpiperazinů. Sloučeniny z této skupiny vysokou afinitu jak vůči dopaminovému D2 receptoru, tak vůči místu reabsorpce serotoninu. Tato kombinace je použitelná k léčení schizofrenie a dalších psychotických onemocnění a umožňuje kompletnější léčbu všech symptomů onemocnění (např. pozitivních symptomů a negativních symptomů).
Sloučeniny vykazují účinky antagonistů dopaminových D2 receptorů, neboť potenciálně antagonizují apomorfinem vyvolané chování ve smyslu šplhání u myši. Sloučeniny též vykazují účinky inhibitorů reabsorpce serotoninu, protože zesilují pomocí 5-HTP vyvolané chování u myši.
• · • ··
Sloučeniny jsou účinné v terapeutických modelech senzitivních vůči klinicky relevantním antipsychotikům (např. podmíněná vyhýbací reakce; Van der Heyden & Bradford, Behav. Brain Res., 1988, 31: 61 až 67) a antidepresívům či anxiolytikům (např. suprese stresem vyvolané vokalizace; van der Poel a kol., Psychofarmacology, 1989, 97: 147 až 148).
Oproti klinicky relevantním antagonistům dopaminových D2 receptorů mají popisované sloučeniny nízký sklon vyvolat katalepsii u hlodavců a jako takové pravděpodobně vyvolávají méně extrapyramidálních vedlejších účinků než existující antipsychotická činidla.
Inhibiční aktivita na reabsorpci serotoninu vlastní těmto sloučeninám může být zodpovědná za terapeutické účinky pozorované v modelech chování senzitivních buď vůči antidepresívům nebo vůči anxiolytikům.
Sloučeniny lze použít k léčení afekcí nebo chorob centrálního nervového systému způsobených buď poruchami dopaminergního nebo serotoninergního systému, např.: agrese, úzkostných poruch, autismu, vertiga, deprese, kognitivních poruch či poruch paměti, Parkinsonovy choroby a zejména schizofrénie a dalších psychotických onemocnění.
Podstata vynálezu
Nyní bylo zjištěno, že mesylát výše uvedeného vzorce vykazuje, v porovnání s volnou bází (tj . sloučeninou č. 89 z EP 99202710.2), výhodné vlastnosti.
Sloučenina obsahuje chirální centrum, k předmětu vynálezu patří jak racemícké směsi, tak jednotlivé enanciomery.
Tato mesylátová sloučenina je o mnoho lépe rozpustná ve vodě než volná báze, což vede k dobré biologické dostupnosti.
• « ·· ··· ·
Sloučeninu lze vhodnými způsoby, za použití pomocných látek, jako jsou kapalné či pevné nosné látky, upravit do formy vhodné pro podávání.
, Volnou bázi sloučeniny lze připravit způsobem popsaným 4 v EP 99202710.2.
Volnou bázi lze převést na mesylát v souladu s o sobě známými způsoby vytváření solí.
Vynález je dokreslen pomocí následujícího příkladu provedení vynálezu.
Příklady provedení vynálezu
Příklad
2,0 g (4,7 mmol) volné báze získatelné způsobem popsaným v EP 99202710.2 (sloučenina č. 89) se suspenduje ve 40 ml methanolu. Suspenze se zahřeje na 60 °C a během přibližně dvou minut se přidá roztok 0,45 g (4,7 mmol) kyseliny methansulfonové v 10 ml methanolu. Získá se čirý roztok. Po míchání po dobu 5 minut při 60 °C začíná krystalizace. Roztok se pomalu, během 60 minut, ochladí na 20 °C a míchá se při této teplotě po dobu 30 minut. Během 60 minut se provede další ochlazení na 0 °C a míchá se po dobu 90 minut. Pevná látka se izoluje pomocí filtrace, promyje 5 ml methanolu a během noci se suší při 50 °C za sníženého tlaku. Výtěžek činí 2,17 g (88 %) bíle zbarveného mesylátu.
Claims (3)
1. 8-{4-[3-(5-Fluor-lH-indol-3-yl)propyl]piperazin-l-yl}-2-methyl-4H-benzo[1,4]oxazin-3-on-mesylát vzorce I
2. Farmaceutická nervového systému obsahuje sloučeninu kompozice pro léčení poruch centrálního vyznačující se tím, že podle nároku 1 jako účinnou látku.
3. Způsob léčení poruch centrálního nervového systému vyznačující se tím, že se použije sloučenina podle nároku 1.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP01200610 | 2001-02-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CZ20032171A3 true CZ20032171A3 (cs) | 2003-11-12 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CZ20032171A CZ20032171A3 (cs) | 2001-02-21 | 2002-02-19 | 8-{4-[3-(5-fluor-1H-indol-3-yl)propyl]piperazin-1-yl}-2-methyl-4H-benzo[1,4]oxazin-3-on-mesylát s vysokou afinitou vůči dopaminovému D2 receptoru a místu reabsorpce serotoninu a farmaceutický prostředek s jeho obsahem |
Country Status (24)
| Country | Link |
|---|---|
| US (2) | US6958396B2 (cs) |
| EP (1) | EP1366044B1 (cs) |
| JP (1) | JP4216072B2 (cs) |
| KR (1) | KR100859107B1 (cs) |
| CN (1) | CN1284780C (cs) |
| AR (1) | AR032712A1 (cs) |
| AT (1) | ATE472545T1 (cs) |
| AU (1) | AU2002250983B2 (cs) |
| BR (1) | BR0206162A (cs) |
| CA (1) | CA2430707C (cs) |
| CZ (1) | CZ20032171A3 (cs) |
| DE (1) | DE60236848D1 (cs) |
| DZ (1) | DZ3490A1 (cs) |
| ES (1) | ES2347321T3 (cs) |
| HU (1) | HUP0303330A3 (cs) |
| IL (1) | IL155720A0 (cs) |
| MX (1) | MXPA03007430A (cs) |
| NO (1) | NO325298B1 (cs) |
| NZ (1) | NZ526018A (cs) |
| PL (1) | PL201176B1 (cs) |
| RU (1) | RU2281945C2 (cs) |
| SK (1) | SK10412003A3 (cs) |
| WO (1) | WO2002066473A1 (cs) |
| ZA (1) | ZA200304267B (cs) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ517900A (en) * | 1999-08-23 | 2003-08-29 | Solvay Pharm Bv | Phenylpiperazines useful as serotonin reuptake inhibitors |
| AR032712A1 (es) * | 2001-02-21 | 2003-11-19 | Solvay Pharm Bv | Un mesilato de derivados de fenilpiperazina y composiciones farmaceuticas que lo contienen |
| US7371769B2 (en) | 2004-12-07 | 2008-05-13 | Solvay Pharmaceuticals B.V. | Tetrahydropyridin-4-yl indoles with a combination of affinity for dopamine-D2 receptors and serotonin reuptake sites |
| MX2007006756A (es) * | 2004-12-07 | 2007-11-09 | Solvay Pharm Bv | Fenilpiperazinas con una afinidad combinada para receptores de dopamina-d2 y sitios de reabsorcion de serotonina. |
| US20070072870A2 (en) | 2004-12-08 | 2007-03-29 | Solvay Pharmeceuticals B.V. | Phenylpiperazine derivatives with a combination of partial dopamine-d2 receptor agonism and serotonin reuptake inhibition |
| GT200600414A (es) * | 2005-09-12 | 2007-09-20 | Sal de glucuranato de compuesto de piperazine | |
| PE20070523A1 (es) | 2005-09-12 | 2007-06-28 | Wyeth Corp | Formulacion de liberacion sostenida del glucuronato de (8-{4-[3-(5-fluoro-1h-indol-3-il)-propil]-piperazin-1-il}-2-metil-4h-benzo[1,4]oxazin-3-ona |
| GT200600416A (es) | 2005-09-12 | 2007-09-20 | Sales salicilato y gentisato de un compuesto de piperazina | |
| US9066903B2 (en) | 2006-02-28 | 2015-06-30 | The United States Of America As Represented By The Department Of Veterans Affairs | Pharmacological treatment of Parkinson's disease |
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| GB1075156A (en) * | 1963-08-27 | 1967-07-12 | Luso Farmaco Inst | Substituted piperazines |
| SE381564B (sv) * | 1973-03-19 | 1975-12-15 | Stiftelsen Teknisk Hjelp At Ha | Eldriven rullstol |
| US4018440A (en) * | 1975-03-31 | 1977-04-19 | Deutsch Fritz A | Invalid walker with wheel control mechanism |
| US4076270A (en) * | 1976-01-19 | 1978-02-28 | General Motors Corporation | Foldable cambering vehicle |
| US4088199A (en) * | 1976-02-23 | 1978-05-09 | Wolfgang Trautwein | Stabilized three-wheeled vehicle |
| BE841212A (nl) * | 1976-04-28 | 1976-08-16 | Sportvoertuig | |
| US4062558A (en) * | 1976-07-19 | 1977-12-13 | David Wasserman | Unicycle |
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| DE2915387A1 (de) * | 1979-04-14 | 1980-10-16 | Heinz Eichholz | Elektrofahrzeug |
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-
2002
- 2002-02-18 AR ARP020100548A patent/AR032712A1/es not_active Application Discontinuation
- 2002-02-19 EP EP02719880A patent/EP1366044B1/en not_active Expired - Lifetime
- 2002-02-19 RU RU2003114440/04A patent/RU2281945C2/ru not_active IP Right Cessation
- 2002-02-19 KR KR1020037010907A patent/KR100859107B1/ko not_active Expired - Fee Related
- 2002-02-19 JP JP2002565987A patent/JP4216072B2/ja not_active Expired - Fee Related
- 2002-02-19 BR BR0206162-7A patent/BR0206162A/pt not_active Application Discontinuation
- 2002-02-19 PL PL362288A patent/PL201176B1/pl not_active IP Right Cessation
- 2002-02-19 CZ CZ20032171A patent/CZ20032171A3/cs unknown
- 2002-02-19 ES ES02719880T patent/ES2347321T3/es not_active Expired - Lifetime
- 2002-02-19 HU HU0303330A patent/HUP0303330A3/hu unknown
- 2002-02-19 IL IL15572002A patent/IL155720A0/xx not_active IP Right Cessation
- 2002-02-19 US US10/432,225 patent/US6958396B2/en not_active Expired - Fee Related
- 2002-02-19 AT AT02719880T patent/ATE472545T1/de not_active IP Right Cessation
- 2002-02-19 DZ DZ023490A patent/DZ3490A1/fr active
- 2002-02-19 MX MXPA03007430A patent/MXPA03007430A/es active IP Right Grant
- 2002-02-19 CN CNB028029682A patent/CN1284780C/zh not_active Expired - Fee Related
- 2002-02-19 CA CA2430707A patent/CA2430707C/en not_active Expired - Fee Related
- 2002-02-19 DE DE60236848T patent/DE60236848D1/de not_active Expired - Lifetime
- 2002-02-19 AU AU2002250983A patent/AU2002250983B2/en not_active Ceased
- 2002-02-19 NZ NZ526018A patent/NZ526018A/en unknown
- 2002-02-19 WO PCT/EP2002/001795 patent/WO2002066473A1/en not_active Ceased
- 2002-02-19 SK SK1041-2003A patent/SK10412003A3/sk unknown
-
2003
- 2003-05-30 ZA ZA200304267A patent/ZA200304267B/en unknown
- 2003-06-24 NO NO20032914A patent/NO325298B1/no not_active IP Right Cessation
-
2005
- 2005-05-23 US US11/134,455 patent/US8106044B2/en not_active Expired - Fee Related
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