FI106455B - Menetelmä kiteisen (alfaS,3R,4R)-4-(3-hydroksifenyyli)-3,4-dimetyyli-alfa-(fenyylimetyyli)-1-piperidiinipropionihappomonohydraatin valmistamiseksi ja kiteiset välituotteet - Google Patents
Menetelmä kiteisen (alfaS,3R,4R)-4-(3-hydroksifenyyli)-3,4-dimetyyli-alfa-(fenyylimetyyli)-1-piperidiinipropionihappomonohydraatin valmistamiseksi ja kiteiset välituotteet Download PDFInfo
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- FI106455B FI106455B FI945703A FI945703A FI106455B FI 106455 B FI106455 B FI 106455B FI 945703 A FI945703 A FI 945703A FI 945703 A FI945703 A FI 945703A FI 106455 B FI106455 B FI 106455B
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- Finland
- Prior art keywords
- crystalline
- acid
- alkyl
- dimethyl
- compound
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- 239000000543 intermediate Substances 0.000 title claims abstract description 15
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 title claims description 13
- 238000000034 method Methods 0.000 title abstract description 35
- 230000008569 process Effects 0.000 title description 21
- 238000002360 preparation method Methods 0.000 title description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 title description 3
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- 125000000217 alkyl group Chemical group 0.000 claims description 44
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical 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)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US16407493 | 1993-12-08 | ||
| US08/164,074 US5434171A (en) | 1993-12-08 | 1993-12-08 | Preparation of 3,4,4-trisubstituted-piperidinyl-N-alkylcarboxylates and intermediates |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| FI945703A0 FI945703A0 (fi) | 1994-12-02 |
| FI945703L FI945703L (fi) | 1995-06-09 |
| FI106455B true FI106455B (fi) | 2001-02-15 |
Family
ID=22592858
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI945703A FI106455B (fi) | 1993-12-08 | 1994-12-02 | Menetelmä kiteisen (alfaS,3R,4R)-4-(3-hydroksifenyyli)-3,4-dimetyyli-alfa-(fenyylimetyyli)-1-piperidiinipropionihappomonohydraatin valmistamiseksi ja kiteiset välituotteet |
| FI20000353A FI106860B (fi) | 1993-12-08 | 2000-02-17 | Menetelmä kiteisen dihydraattiyhdisteen valmistamiseksi ja kiteinen välituote |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI20000353A FI106860B (fi) | 1993-12-08 | 2000-02-17 | Menetelmä kiteisen dihydraattiyhdisteen valmistamiseksi ja kiteinen välituote |
Country Status (30)
| Country | Link |
|---|---|
| US (1) | US5434171A (en, 2012) |
| EP (3) | EP0657428B1 (en, 2012) |
| JP (2) | JP3834075B2 (en, 2012) |
| KR (1) | KR100356239B1 (en, 2012) |
| CN (2) | CN1057294C (en, 2012) |
| AT (1) | ATE200279T1 (en, 2012) |
| AU (1) | AU681198B2 (en, 2012) |
| BR (1) | BR9404842A (en, 2012) |
| CA (1) | CA2137221C (en, 2012) |
| CO (1) | CO4290427A1 (en, 2012) |
| CZ (1) | CZ290559B6 (en, 2012) |
| DE (1) | DE69427017T2 (en, 2012) |
| DK (1) | DK0657428T3 (en, 2012) |
| ES (1) | ES2155844T3 (en, 2012) |
| FI (2) | FI106455B (en, 2012) |
| GR (1) | GR3036136T3 (en, 2012) |
| HU (1) | HUT71489A (en, 2012) |
| IL (1) | IL111843A (en, 2012) |
| MY (1) | MY121543A (en, 2012) |
| NO (1) | NO302884B1 (en, 2012) |
| NZ (1) | NZ270039A (en, 2012) |
| PE (1) | PE41495A1 (en, 2012) |
| PL (1) | PL181734B1 (en, 2012) |
| PT (1) | PT657428E (en, 2012) |
| RU (1) | RU2145958C1 (en, 2012) |
| SI (1) | SI0657428T1 (en, 2012) |
| TW (1) | TW290540B (en, 2012) |
| UA (1) | UA52577C2 (en, 2012) |
| YU (2) | YU49312B (en, 2012) |
| ZA (1) | ZA949584B (en, 2012) |
Families Citing this family (64)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2722497B1 (fr) * | 1994-07-13 | 1996-08-14 | Synthelabo | Esters de alpha-4-chlorophenyl)-4-(4-fluorophenyl)methyl) piperidine-1-ethanol, leur preparation et leur application en therapeutique |
| HN1999000149A (es) * | 1998-09-09 | 2000-01-12 | Pfizer Prod Inc | Derivados de 4,4-biarilpiperidina |
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| GB9912413D0 (en) | 1999-05-28 | 1999-07-28 | Pfizer Ltd | Compounds useful in therapy |
| GB9912415D0 (en) | 1999-05-28 | 1999-07-28 | Pfizer Ltd | Compounds useful in therapy |
| GB9912411D0 (en) | 1999-05-28 | 1999-07-28 | Pfizer Ltd | Compounds useful in therapy |
| GB9912417D0 (en) | 1999-05-28 | 1999-07-28 | Pfizer Ltd | Compounds useful in therapy |
| GB9912416D0 (en) | 1999-05-28 | 1999-07-28 | Pfizer Ltd | Compounds useful in therapy |
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| US6469030B2 (en) | 1999-11-29 | 2002-10-22 | Adolor Corporation | Methods for the treatment and prevention of ileus |
| CA2449175A1 (en) * | 2001-06-05 | 2002-12-12 | University Of Chicago | Use of methylnaltrexone to treat immune suppression |
| US20030068829A1 (en) * | 2001-06-25 | 2003-04-10 | Symyx Technologies, Inc. | High throughput crystallographic screening of materials |
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| US6794510B2 (en) * | 2002-08-08 | 2004-09-21 | Adolor Corporation | Processes for the preparation of peripheral opioid antagonist compounds and intermediates thereto |
| US7381721B2 (en) * | 2003-03-17 | 2008-06-03 | Adolor Corporation | Substituted piperidine compounds |
| WO2004091622A1 (en) * | 2003-04-08 | 2004-10-28 | Progenics Pharmaceuticals, Inc. | The use of peripheral opiois antagonists, especially methylnaltrexone to treat irritable bowel syndrome |
| PT2368553E (pt) | 2003-04-08 | 2015-03-03 | Progenics Pharm Inc | Formulações farmacêuticas contendo metilnaltrexona |
| US6992090B2 (en) * | 2003-06-16 | 2006-01-31 | Adolor Corporation | Substituted piperidine compounds and methods of their use |
| FR2861304B1 (fr) * | 2003-10-23 | 2008-07-18 | Univ Grenoble 1 | Modulateurs des canaux cftr |
| US20050148630A1 (en) * | 2003-12-02 | 2005-07-07 | Carpenter Randall L. | Methods of preventing and treating non-opioid induced gastrointestinal dysfunction |
| US8946262B2 (en) * | 2003-12-04 | 2015-02-03 | Adolor Corporation | Methods of preventing and treating gastrointestinal dysfunction |
| EA018427B1 (ru) * | 2003-12-16 | 2013-07-30 | Нектар Терапьютикс | Химически модифицированный налоксон |
| US20060182692A1 (en) * | 2003-12-16 | 2006-08-17 | Fishburn C S | Chemically modified small molecules |
| US7087749B2 (en) * | 2004-03-11 | 2006-08-08 | Adolor Corporation | Substituted piperidine compounds and methods of their use |
| US20050240177A1 (en) * | 2004-04-26 | 2005-10-27 | Packaging Service Corporation Of Kentucky | Electrosurgical forceps |
| US7700626B2 (en) | 2004-06-04 | 2010-04-20 | Adolor Corporation | Compositions containing opioid antagonists |
| US8039456B2 (en) | 2004-08-12 | 2011-10-18 | Helsinn Therapeutics (U.S.), Inc. | Method of stimulating the motility of the gastrointestinal system using ipamorelin |
| CN101076349B (zh) * | 2004-08-12 | 2012-08-22 | 蓝宝石治疗公司 | 生长激素促分泌素用于制备刺激胃肠系统动力的药物的用途 |
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| AR057325A1 (es) | 2005-05-25 | 2007-11-28 | Progenics Pharm Inc | Sintesis de (s)-n-metilnaltrexona, composiciones farmaceuticas y usos |
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| EP2034977B1 (en) | 2006-04-21 | 2011-07-13 | DSM IP Assets B.V. | Use of opioid receptor antagonists |
| TWI489984B (zh) | 2006-08-04 | 2015-07-01 | Wyeth Corp | 用於非經腸道傳輸化合物之配方及其用途 |
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| CL2008000905A1 (es) | 2007-03-29 | 2008-08-22 | Progenics Pharm Inc | Compuestos derivados de morfina, antagonistas del receptor opioide periferico; metodo de preparacion; composicion farmaceutica; y uso para reducir los efectos de la actividad opioide endogena. |
| ES2540551T3 (es) | 2007-03-29 | 2015-07-10 | Wyeth Llc | Antagonistas de receptores opioides periféricos y usos de los mismos |
| JP5358587B2 (ja) | 2008-02-06 | 2013-12-04 | プロジェニックス・ファーマシューティカルス・インコーポレイテッド | （ｒ），（ｒ）−２，２’−ビス−メチルナルトレキソンの製造及び用途 |
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| CA2676881C (en) | 2008-09-30 | 2017-04-25 | Wyeth | Peripheral opioid receptor antagonists and uses thereof |
| CN101429154B (zh) * | 2008-11-14 | 2011-01-05 | 天津泰普药品科技发展有限公司 | 无水阿维莫泮及其药物组合物 |
| US20100311782A1 (en) | 2009-06-08 | 2010-12-09 | Adolor Corporation | Substituted piperidinylpropanoic acid compounds and methods of their use |
| SMT201900357T1 (it) | 2009-12-04 | 2019-07-11 | Alkermes Pharma Ireland Ltd | Derivati di morfinano per trattamento di abuso di sostanze stupefacenti |
| WO2011161646A2 (en) | 2010-06-25 | 2011-12-29 | Ranbaxy Laboratories Limited | Process for the preparation of alvimopan or its pharmaceutically acceptable salt or solvate thereof |
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| CN103360302B (zh) * | 2012-03-29 | 2015-08-26 | 北大方正集团有限公司 | 阿维莫泮的纯化方法 |
| WO2016064914A1 (en) | 2014-10-20 | 2016-04-28 | Elysium Therapeutics, Inc. | Diversion-resistant opioid formulations |
| JP2018534269A (ja) | 2015-10-01 | 2018-11-22 | エリージウム セラピューティクス， インコーポレイテッド | 過剰摂取および乱用に抵抗性のポリサブユニットオピオイドプロドラッグ |
| US10335406B2 (en) | 2015-10-01 | 2019-07-02 | Elysium Therapeutics, Inc. | Opioid compositions resistant to overdose and abuse |
| EP3595663A4 (en) | 2017-03-17 | 2021-01-13 | Elysium Therapeutics, Inc. | MULTI-UNIT OPIOID MEDICINES RESISTANT TO OVERDOSE AND ABUSE |
| WO2024090512A1 (ja) * | 2022-10-27 | 2024-05-02 | 株式会社京都創薬研究所 | ナフタレン誘導体の結晶 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4891379A (en) * | 1987-04-16 | 1990-01-02 | Kabushiki Kaisha Kobe Seikosho | Piperidine opioid antagonists |
| US5136040A (en) * | 1991-02-26 | 1992-08-04 | Eli Lilly And Company | Preparation of substituted tetrahydropyridines |
| US5250542A (en) * | 1991-03-29 | 1993-10-05 | Eli Lilly And Company | Peripherally selective piperidine carboxylate opioid antagonists |
| NZ242117A (en) * | 1991-03-29 | 1994-11-25 | Lilly Co Eli | 4-phenylpiperidine derivatives and medicaments containing them |
| US5159081A (en) * | 1991-03-29 | 1992-10-27 | Eli Lilly And Company | Intermediates of peripherally selective n-carbonyl-3,4,4-trisubstituted piperidine opioid antagonists |
-
1993
- 1993-12-08 US US08/164,074 patent/US5434171A/en not_active Expired - Lifetime
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1994
- 1994-12-01 ZA ZA949584A patent/ZA949584B/xx unknown
- 1994-12-01 NZ NZ270039A patent/NZ270039A/en not_active IP Right Cessation
- 1994-12-01 IL IL11184394A patent/IL111843A/xx not_active IP Right Cessation
- 1994-12-01 PE PE1994256135A patent/PE41495A1/es not_active Application Discontinuation
- 1994-12-01 AU AU79170/94A patent/AU681198B2/en not_active Ceased
- 1994-12-01 CZ CZ19942992A patent/CZ290559B6/cs not_active IP Right Cessation
- 1994-12-01 JP JP29835694A patent/JP3834075B2/ja not_active Expired - Fee Related
- 1994-12-01 TW TW083111189A patent/TW290540B/zh not_active IP Right Cessation
- 1994-12-01 PL PL94306068A patent/PL181734B1/pl not_active IP Right Cessation
- 1994-12-02 CO CO94055028A patent/CO4290427A1/es unknown
- 1994-12-02 DK DK94308951T patent/DK0657428T3/da active
- 1994-12-02 HU HU9403466A patent/HUT71489A/hu unknown
- 1994-12-02 FI FI945703A patent/FI106455B/fi not_active IP Right Cessation
- 1994-12-02 DE DE69427017T patent/DE69427017T2/de not_active Expired - Lifetime
- 1994-12-02 BR BR9404842A patent/BR9404842A/pt not_active Application Discontinuation
- 1994-12-02 AT AT94308951T patent/ATE200279T1/de not_active IP Right Cessation
- 1994-12-02 ES ES94308951T patent/ES2155844T3/es not_active Expired - Lifetime
- 1994-12-02 PT PT94308951T patent/PT657428E/pt unknown
- 1994-12-02 EP EP94308951A patent/EP0657428B1/en not_active Expired - Lifetime
- 1994-12-02 SI SI9430367T patent/SI0657428T1/xx unknown
- 1994-12-02 NO NO944644A patent/NO302884B1/no not_active IP Right Cessation
- 1994-12-02 YU YU70294A patent/YU49312B/sh unknown
- 1994-12-02 EP EP05077072A patent/EP1607387A3/en not_active Withdrawn
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- 1994-12-02 UA UA94129124A patent/UA52577C2/uk unknown
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- 1994-12-03 CN CN94119376A patent/CN1057294C/zh not_active Expired - Fee Related
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1998
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