PT1467993E - Processo para a preparação de ésteres de escopina - Google Patents
Processo para a preparação de ésteres de escopina Download PDFInfo
- Publication number
- PT1467993E PT1467993E PT02796735T PT02796735T PT1467993E PT 1467993 E PT1467993 E PT 1467993E PT 02796735 T PT02796735 T PT 02796735T PT 02796735 T PT02796735 T PT 02796735T PT 1467993 E PT1467993 E PT 1467993E
- Authority
- PT
- Portugal
- Prior art keywords
- formula
- esters
- quaternized scopine
- scopine
- quaternized
- Prior art date
Links
- FIMXSEMBHGTNKT-RZVDLVGDSA-N scopine Chemical class C([C@@H]1N2C)[C@H](O)C[C@@H]2[C@@H]2[C@H]1O2 FIMXSEMBHGTNKT-RZVDLVGDSA-N 0.000 title abstract 3
- 238000004519 manufacturing process Methods 0.000 title abstract 2
- -1 scopine compound Chemical class 0.000 abstract 4
- FIMXSEMBHGTNKT-UHFFFAOYSA-N Scopine Natural products CN1C2CC(O)CC1C1C2O1 FIMXSEMBHGTNKT-UHFFFAOYSA-N 0.000 abstract 3
- 239000002253 acid Substances 0.000 abstract 3
- 125000003545 alkoxy group Chemical group 0.000 abstract 2
- 125000000217 alkyl group Chemical group 0.000 abstract 2
- 150000002148 esters Chemical class 0.000 abstract 2
- 230000001088 anti-asthma Effects 0.000 abstract 1
- 230000001078 anti-cholinergic effect Effects 0.000 abstract 1
- 230000003110 anti-inflammatory effect Effects 0.000 abstract 1
- 239000000924 antiasthmatic agent Substances 0.000 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- 125000002541 furyl group Chemical group 0.000 abstract 1
- 230000010534 mechanism of action Effects 0.000 abstract 1
- 125000001624 naphthyl group Chemical group 0.000 abstract 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- 125000001544 thienyl group Chemical group 0.000 abstract 1
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
- C07D491/12—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 three hetero rings
- C07D491/18—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
- C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
-
- 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
-
- 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
-
- 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
- C07D491/02—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 two hetero rings
- C07D491/08—Bridged systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pulmonology (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Indole Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Polyethers (AREA)
- Hydrogenated Pyridines (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10200943A DE10200943A1 (de) | 2002-01-12 | 2002-01-12 | Verfahren zur Herstellung von Scopinestern |
Publications (1)
Publication Number | Publication Date |
---|---|
PT1467993E true PT1467993E (pt) | 2008-09-03 |
Family
ID=7711974
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PT02796735T PT1467993E (pt) | 2002-01-12 | 2002-12-24 | Processo para a preparação de ésteres de escopina |
Country Status (31)
Country | Link |
---|---|
US (1) | US6747154B2 (pt) |
EP (2) | EP1972626A3 (pt) |
JP (1) | JP5134756B2 (pt) |
KR (1) | KR100929503B1 (pt) |
CN (1) | CN100406456C (pt) |
AT (1) | ATE404557T1 (pt) |
AU (1) | AU2002361218B2 (pt) |
BR (1) | BR0215493A (pt) |
CA (1) | CA2471755C (pt) |
CO (1) | CO5601006A2 (pt) |
CY (1) | CY1108471T1 (pt) |
DE (2) | DE10200943A1 (pt) |
DK (1) | DK1467993T3 (pt) |
EA (1) | EA007230B1 (pt) |
EC (1) | ECSP045182A (pt) |
ES (1) | ES2312655T3 (pt) |
HK (1) | HK1073847A1 (pt) |
HR (1) | HRP20040623B1 (pt) |
HU (1) | HU226665B1 (pt) |
IL (2) | IL162416A0 (pt) |
ME (1) | MEP51208A (pt) |
MX (1) | MXPA04006677A (pt) |
NO (1) | NO328825B1 (pt) |
NZ (1) | NZ534339A (pt) |
PL (1) | PL208132B1 (pt) |
PT (1) | PT1467993E (pt) |
RS (1) | RS50771B (pt) |
SI (1) | SI1467993T1 (pt) |
UA (1) | UA78753C2 (pt) |
WO (1) | WO2003057694A1 (pt) |
ZA (1) | ZA200403852B (pt) |
Families Citing this family (42)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10141377A1 (de) | 2001-08-23 | 2003-03-13 | Boehringer Ingelheim Pharma | Aufstreuverfahren zur Herstellung von Pulverformulierungen |
US7417051B2 (en) * | 2002-04-12 | 2008-08-26 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Medicaments comprising betamimetics and a novel anticholinergic |
US7084153B2 (en) * | 2002-04-12 | 2006-08-01 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Medicaments comprising steroids and a novel anticholinergic |
DE10216427A1 (de) * | 2002-04-12 | 2003-10-23 | Boehringer Ingelheim Pharma | Arzneimittelkompositionen enthaltend heterocyclische Verbindungen und ein neues Anticholinergikum |
US20040044020A1 (en) * | 2002-07-09 | 2004-03-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical compositions based on novel anticholinergics and p38 kinase inhibitors |
US20040058950A1 (en) * | 2002-07-09 | 2004-03-25 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical compositions based on anticholinergics and PDE-IV inhibitors |
US20040048887A1 (en) * | 2002-07-09 | 2004-03-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical compositions based on anticholinergics and EGFR kinase inhibitors |
US20040048886A1 (en) * | 2002-07-09 | 2004-03-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical compositions based on new anticholinergics and NK1 receptor antagonists |
US20040166065A1 (en) | 2002-08-14 | 2004-08-26 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Aerosol formulation for inhalation comprising an anticholinergic |
DK1530464T3 (da) * | 2002-08-14 | 2008-09-08 | Boehringer Ingelheim Pharma | Aerosolformulering til inhalation med indhold af et anticholinergikum |
US7244742B2 (en) * | 2002-08-17 | 2007-07-17 | Boehringer Ingelheim Pharma Gmbh & Co Kg | Pharmaceutical compositions for inhalation containing an anticholinergic, corticosteroid and betamimetic |
US7056916B2 (en) * | 2002-11-15 | 2006-06-06 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Medicaments for the treatment of chronic obstructive pulmonary disease |
US7332175B2 (en) * | 2003-05-27 | 2008-02-19 | Boehringer Ingelheim International Gmbh | Long-acting drug combinations for the treatment of respiratory complaints |
US7273603B2 (en) * | 2003-07-11 | 2007-09-25 | Boehringer Ingelheim International Gmbh | HFC solution formulations containing an anticholinergic |
JP2007500676A (ja) * | 2003-07-31 | 2007-01-18 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 抗コリン作用薬とベータ受容体刺激薬を含む吸入用薬剤 |
US20050025718A1 (en) * | 2003-07-31 | 2005-02-03 | Boehringer Ingelheim International Gmbh | Medicaments for inhalation comprising an anticholinergic and a betamimetic |
SG137859A1 (en) * | 2003-11-03 | 2007-12-28 | Boehringer Ingelheim Int | Method for producing tiotropium salts, tiotropium salts and pharmaceutical formulations, containing the same |
UY28589A1 (es) * | 2003-11-03 | 2005-06-30 | Boehringer Ingelheim Int | Nuevas sales de tiotropio, procedimientos para su preparación , así como formulaciones medicamentosas que las contienen |
US20050272726A1 (en) * | 2004-04-22 | 2005-12-08 | Boehringer Ingelheim International Gmbh | Novel medicaments for the treatment of respiratory diseases |
US7220742B2 (en) * | 2004-05-14 | 2007-05-22 | Boehringer Ingelheim International Gmbh | Enantiomerically pure beta agonists, process for the manufacture thereof and use thereof as medicaments |
US20050255050A1 (en) * | 2004-05-14 | 2005-11-17 | Boehringer Ingelheim International Gmbh | Powder formulations for inhalation, comprising enantiomerically pure beta agonists |
US20050256115A1 (en) * | 2004-05-14 | 2005-11-17 | Boehringer Ingelheim International Gmbh | Aerosol formulation for the inhalation of beta-agonists |
DE102004041253A1 (de) | 2004-08-26 | 2006-03-02 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neues Verfahren zur Herstellung von Tiotropiumsalzen |
JP5227790B2 (ja) * | 2005-05-02 | 2013-07-03 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 新規結晶性臭化チオトロピウム |
EP1896026B1 (en) * | 2005-06-15 | 2013-10-09 | Boehringer Ingelheim International GmbH | Process for preparing tiotropium salts, tiotropium salts as such and pharmaceutical compositions thereof |
DE102005035112A1 (de) * | 2005-07-27 | 2007-02-15 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neues Verfahren zur Herstellung von Tiotropiumsalzen unter Anwendung von in organischen Lösungsmitteln löslichen N-Methylscopiniumsalzen |
RU2412176C2 (ru) * | 2005-08-15 | 2011-02-20 | Бёрингер Ингельхайм Интернациональ Гмбх | Способ получения бетамиметиков |
WO2008089852A1 (de) * | 2007-01-26 | 2008-07-31 | Boehringer Ingelheim Pharma Gmbh & Co.Kg | Neues verfahren zur herstellung von tiotropiumsalzen |
EP1953156A1 (de) * | 2007-01-29 | 2008-08-06 | Boehringer Ingelheim Pharma GmbH & Co. KG | Verfahren zur Herstellung von Scopiniumsalzen |
EP1997819A1 (de) * | 2007-05-25 | 2008-12-03 | Boehringer Ingelheim Pharma GmbH & Co. KG | Verfahren zur Herstellung von Scopinestern |
PL2240477T3 (pl) * | 2008-01-10 | 2015-03-31 | Generics Uk Ltd | Nowy sposób wytwarzania estrów skopiny |
US8263623B2 (en) | 2008-07-11 | 2012-09-11 | Pfizer Inc. | Triazol derivatives useful for the treatment of diseases |
NZ624602A (en) | 2009-08-07 | 2015-11-27 | Generics Uk Ltd | Anhydrate of tiotropium bromide |
WO2011015884A1 (en) * | 2009-08-07 | 2011-02-10 | Generics [Uk] Limited | Process to prepare scopine esters |
TR201005221A2 (tr) * | 2010-04-01 | 2012-01-23 | Bi̇lgi̇ç Mahmut | Geliştirilmiş sentez metodu. |
TR201005222A2 (tr) * | 2010-04-01 | 2011-10-21 | Bi̇lgi̇ç Mahmut | Tiotropyum bromür sentez yöntemi |
US8957209B2 (en) | 2010-04-01 | 2015-02-17 | Mahmut Bilgic | Methods for the synthesis of tiotropium bromide |
TR201002520A2 (tr) * | 2010-04-01 | 2010-05-21 | Bi̇lgi̇ç Mahmut | Tiotropyum bromür imalat metodu. |
ITRM20110508A1 (it) | 2011-09-27 | 2013-03-28 | Lusochimica Spa | Processo per la preparazione degli esteri della scopina. |
PT106142B (pt) | 2012-02-10 | 2014-07-18 | Hovione Farmaci Ncia S A | Processo para a preparação de brometo de tiotrópio |
CZ304808B6 (cs) | 2012-03-16 | 2014-11-05 | Zentiva, K.S. | Způsob přípravy skopinesteru kyseliny di(2-thienyl)glykolové, intermediátu v syntéze tiotropium bromidu a jeho nová forma |
CZ305012B6 (cs) | 2012-03-30 | 2015-03-25 | Zentiva, K.S. | Způsob přípravy skopinesteru kyseliny di(2-thienyl)glykolové, intermediátu v syntéze tiotropium bromidu |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2540633A1 (de) | 1975-09-12 | 1977-04-28 | Boehringer Sohn Ingelheim | Neue quartaere n-beta-substituierte benzilsaeure-n-alkyl-nortropinester und verfahren zu deren herstellung |
DE3211185A1 (de) | 1982-03-26 | 1983-09-29 | Boehringer Ingelheim KG, 6507 Ingelheim | Neue quartaere 6,11-dihydro-dibenzo-(b,e)-thiepin-11-n-alkyl- norscopinether und verfahren zu deren herstellung |
DE3215493A1 (de) | 1982-04-26 | 1983-11-03 | Boehringer Ingelheim KG, 6507 Ingelheim | Neue zwischenprodukte, verfahren zu ihrer herstellung und ihre verwendung |
US5610163A (en) | 1989-09-16 | 1997-03-11 | Boehringer Ingelheim Gmbh | Esters of thienyl carboxylic acids and amino alcohols and their quaternization products |
DE3931041C2 (de) * | 1989-09-16 | 2000-04-06 | Boehringer Ingelheim Kg | Ester von Thienylcarbonsäuren mit Aminoalkoholen, ihre Quaternierungsprodukte, Verfahren zu ihrer Herstellung und diese enthaltende Arzneimittel |
DE4108393A1 (de) | 1991-03-15 | 1992-09-17 | Boehringer Ingelheim Kg | Neue ester bi- und tricyclischer aminoalkohole, ihre herstellung und ihre verwendung in arzneimitteln |
US5770738A (en) | 1992-03-05 | 1998-06-23 | Boehringer Ingelheim Kg | Esters of bi- and tricyclic amino alcohols, their preparation and their use in pharmaceutical compositions |
UA49801C2 (uk) * | 1994-04-19 | 2002-10-15 | Нейросерч А/С | Похідні тропан-2-альдоксиму, спосіб їх отримання, фармацевтична композиція, спосіб лікування |
DE19515625C2 (de) | 1995-04-28 | 1998-02-19 | Boehringer Ingelheim Kg | Verfahren zur Herstellung von enantiomerenreinen Tropasäureestern |
WO1998016528A1 (en) * | 1996-10-11 | 1998-04-23 | Chiron Corporation | Purine inhibitors of glycogen synthase kinase 3 (gsk3) |
DE10050995A1 (de) * | 2000-10-14 | 2002-04-18 | Boehringer Ingelheim Pharma | Neue Anticholinergika, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel |
DE10050994A1 (de) * | 2000-10-14 | 2002-04-18 | Boehringer Ingelheim Pharma | Neue als Arneimittel einsetzbare Anticholinergika sowie Verfahren zu deren Herstellung |
DE10064816A1 (de) * | 2000-12-22 | 2002-06-27 | Boehringer Ingelheim Pharma | Verfahren zur Herstellung eines Anticholinergikums |
US6506900B1 (en) | 2001-01-31 | 2003-01-14 | Boehringer Ingelheim Pharma Ag | Process for preparing a scopine ester intermediate |
-
2002
- 2002-01-12 DE DE10200943A patent/DE10200943A1/de not_active Withdrawn
- 2002-12-24 WO PCT/EP2002/014756 patent/WO2003057694A1/de active IP Right Grant
- 2002-12-24 JP JP2003558009A patent/JP5134756B2/ja not_active Expired - Fee Related
- 2002-12-24 MX MXPA04006677A patent/MXPA04006677A/es active IP Right Grant
- 2002-12-24 AU AU2002361218A patent/AU2002361218B2/en not_active Ceased
- 2002-12-24 PT PT02796735T patent/PT1467993E/pt unknown
- 2002-12-24 BR BR0215493-5A patent/BR0215493A/pt not_active Expired - Fee Related
- 2002-12-24 NZ NZ534339A patent/NZ534339A/en not_active IP Right Cessation
- 2002-12-24 ME MEP-512/08A patent/MEP51208A/xx unknown
- 2002-12-24 DK DK02796735T patent/DK1467993T3/da active
- 2002-12-24 IL IL16241602A patent/IL162416A0/xx unknown
- 2002-12-24 CA CA2471755A patent/CA2471755C/en not_active Expired - Fee Related
- 2002-12-24 KR KR1020047010736A patent/KR100929503B1/ko not_active IP Right Cessation
- 2002-12-24 PL PL369126A patent/PL208132B1/pl not_active IP Right Cessation
- 2002-12-24 HU HU0402604A patent/HU226665B1/hu not_active IP Right Cessation
- 2002-12-24 CN CNB028265610A patent/CN100406456C/zh not_active Expired - Fee Related
- 2002-12-24 AT AT02796735T patent/ATE404557T1/de active
- 2002-12-24 EA EA200400875A patent/EA007230B1/ru not_active IP Right Cessation
- 2002-12-24 UA UA20040806731A patent/UA78753C2/uk unknown
- 2002-12-24 SI SI200230756T patent/SI1467993T1/sl unknown
- 2002-12-24 EP EP08159580A patent/EP1972626A3/de not_active Withdrawn
- 2002-12-24 ES ES02796735T patent/ES2312655T3/es not_active Expired - Lifetime
- 2002-12-24 DE DE50212650T patent/DE50212650D1/de not_active Expired - Lifetime
- 2002-12-24 EP EP02796735A patent/EP1467993B1/de not_active Expired - Lifetime
- 2002-12-24 RS YUP-594/04A patent/RS50771B/sr unknown
-
2003
- 2003-01-09 US US10/339,480 patent/US6747154B2/en not_active Expired - Lifetime
-
2004
- 2004-05-19 ZA ZA200403852A patent/ZA200403852B/en unknown
- 2004-06-09 IL IL162416A patent/IL162416A/en not_active IP Right Cessation
- 2004-07-09 HR HRP20040623AA patent/HRP20040623B1/xx not_active IP Right Cessation
- 2004-07-12 EC EC2004005182A patent/ECSP045182A/es unknown
- 2004-07-23 CO CO04070837A patent/CO5601006A2/es not_active Application Discontinuation
- 2004-08-11 NO NO20043341A patent/NO328825B1/no not_active IP Right Cessation
-
2005
- 2005-07-29 HK HK05106514A patent/HK1073847A1/xx not_active IP Right Cessation
-
2008
- 2008-10-31 CY CY20081101236T patent/CY1108471T1/el unknown
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