PE20030866A1 - Inhibidores de tirosina-quinasa para el tratamiento de procesos inflamatorios - Google Patents
Inhibidores de tirosina-quinasa para el tratamiento de procesos inflamatoriosInfo
- Publication number
- PE20030866A1 PE20030866A1 PE2003000121A PE2003000121A PE20030866A1 PE 20030866 A1 PE20030866 A1 PE 20030866A1 PE 2003000121 A PE2003000121 A PE 2003000121A PE 2003000121 A PE2003000121 A PE 2003000121A PE 20030866 A1 PE20030866 A1 PE 20030866A1
- Authority
- PE
- Peru
- Prior art keywords
- amino
- chloro
- phenyl
- quinazoline
- fluoro
- Prior art date
Links
Classifications
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
-
- 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
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- 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
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
Abstract
SE REFIERE A QUINAZOLINAS DE FORMULA I DONDE X ES NITROGENO O CARBONO SUSTITUIDO CON CIANO; Ra ES H, ALQUILO; Rb ES FENILO, BENCILO, 1-FENILETILO OPCIONALMENTE SUSTITUIDOS CON R1 Y R2; R1 Y R2 SON H, F, Cl, Br, I, ALQUILO, HIDROXI, ALCOXI, ENTRE OTROS; A ES OXIGENO O IMINO OPCIONALMENTE SUSTITUIDO CON ALQUILO; B ES UN ENLACE, CARBONILO, SULFONILO; C ES METILENO, ETILENO, ETENILENO; n ES 0-1; D ES AMINO, ALQUIL-AMINO, CICLOALQUIL-AMINO; O COMPUESTOS: 4-[(3-CLORO-4-FLUOROFENIL)AMINO]-6-[(4-DIMETILAMINO-CICLOHEXIL)AMINO]PIRIMIDO[5,4-d]PIRIMIDINA; 4-[(R)-(1-FENILETIL)AMINO]-6-[(4-HIDROXIFENIL)-7H-PIRROLO[2,3-d]PIRIMIDINA; 4-{[3-CLORO-4-(3-FLUORO-4-BENCILOXI)FENIL]AMINO}-6-(5-{[(2-METANOSULFONIL-ETIL)AMINOMETIL}-FURAN-2-IL)-QUINAZOLINA DE LOS ANTICUERPOS CETUXIMAB, TRASTUZUMAB; ABX-EGF, ACMICR-62, EGFR-ANTISENTIDO. SON COMPUESTOS PREFERIDOS: 4-[(3-CLORO-4-FLUORO-FENIL)AMINO]-7-(2-{4-[(S)-(2-OXO-TETRAHIDROFURAN-5-IL)CARBONIL]PIPERAZINA-1-IL}-ETOXI)-6-[(VINILCARBONIL)AMINO]QUINAZOLINA; 4-[(3-CLORO-4-FLUORO-FENIL)AMINO]-7-(4-[(R)-6-METIL-2-OXO-MORFOLIN-4-IL)-BUTILOXI]-6-[(VINILCARBONIL)AMINO]QUINAZOLINA; ENTRE OTROS. LOS COMPUESTOS PUEDEN SER UTILES PARA EL TRATAMIENTO DE ENFERMEDADES DE LAS VIAS RESPIRATORIAS, BRONQUITIS, BRONQUIECTASIAS, RINITIS, SINUSITIS ALERGICA, FIBROSIS QUISTICA
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10204462A DE10204462A1 (de) | 2002-02-05 | 2002-02-05 | Verwendung von Tyrosinkinase-Inhibitoren zur Behandlung inflammatorischer Prozesse |
Publications (1)
Publication Number | Publication Date |
---|---|
PE20030866A1 true PE20030866A1 (es) | 2003-11-28 |
Family
ID=7713648
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PE2003000121A PE20030866A1 (es) | 2002-02-05 | 2003-02-03 | Inhibidores de tirosina-quinasa para el tratamiento de procesos inflamatorios |
Country Status (11)
Country | Link |
---|---|
US (2) | US20030149062A1 (es) |
EP (1) | EP1474149A2 (es) |
JP (1) | JP2005525328A (es) |
AR (1) | AR038392A1 (es) |
AU (1) | AU2003206785A1 (es) |
CA (1) | CA2472293C (es) |
DE (1) | DE10204462A1 (es) |
PE (1) | PE20030866A1 (es) |
TW (1) | TW200404547A (es) |
UY (1) | UY27647A1 (es) |
WO (1) | WO2003066060A2 (es) |
Families Citing this family (48)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
UA71976C2 (en) * | 1999-06-21 | 2005-01-17 | Boehringer Ingelheim Pharma | Bicyclic heterocycles and a medicament based thereon |
US7019012B2 (en) * | 2000-12-20 | 2006-03-28 | Boehringer Ingelheim International Pharma Gmbh & Co. Kg | Quinazoline derivatives and pharmaceutical compositions containing them |
TW200813014A (en) * | 2002-03-28 | 2008-03-16 | Astrazeneca Ab | Quinazoline derivatives |
US6924285B2 (en) * | 2002-03-30 | 2005-08-02 | Boehringer Ingelheim Pharma Gmbh & Co. | Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them |
US7576074B2 (en) | 2002-07-15 | 2009-08-18 | Rice Kenneth D | Receptor-type kinase modulators and methods of use |
US7223749B2 (en) * | 2003-02-20 | 2007-05-29 | Boehringer Ingelheim International Gmbh | Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them |
EP2389953A1 (en) * | 2003-06-09 | 2011-11-30 | Samuel Waksal | Method of inhibiting receptor tyrosine kinases with an extracellular antagonist and an intracellular antagonist |
NZ544472A (en) * | 2003-07-03 | 2009-04-30 | Myriad Genetics Inc | Compounds and therapeutical use thereof |
US8309562B2 (en) | 2003-07-03 | 2012-11-13 | Myrexis, Inc. | Compounds and therapeutical use thereof |
US20050059661A1 (en) * | 2003-07-28 | 2005-03-17 | Boehringer Ingelheim International Gmbh | Use of tyrosine kinase inhibitors for the treatment of inflammatory processes |
GB0317665D0 (en) * | 2003-07-29 | 2003-09-03 | Astrazeneca Ab | Qinazoline derivatives |
EP1660479A1 (en) * | 2003-07-29 | 2006-05-31 | Astrazeneca AB | Piperidyl-quinazoline derivatives as tyrosine kinase inhibitors |
SI1667991T1 (sl) * | 2003-09-16 | 2008-10-31 | Astrazeneca Ab | Kinazolinski derivati kot inhibitorji tirozin kinaze |
ES2279441T3 (es) * | 2003-09-19 | 2007-08-16 | Astrazeneca Ab | Derivados de quinazolina. |
DE602004004811T2 (de) * | 2003-09-19 | 2007-11-22 | Astrazeneca Ab | Chinazolinderivate |
WO2005030757A1 (en) * | 2003-09-25 | 2005-04-07 | Astrazeneca Ab | Quinazoline derivatives |
CA2537812C (en) | 2003-09-26 | 2013-01-22 | Exelixis, Inc. | C-met modulators and method of use |
US7456189B2 (en) * | 2003-09-30 | 2008-11-25 | Boehringer Ingelheim International Gmbh | Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation |
DE10349113A1 (de) * | 2003-10-17 | 2005-05-12 | Boehringer Ingelheim Pharma | Verfahren zur Herstellung von Aminocrotonylverbindungen |
US20050096332A1 (en) * | 2003-10-30 | 2005-05-05 | Boehringer Ingelheim International Gmbh | Use of tyrosine kinase inhibitors for the treatment of inflammatory processes |
NZ546942A (en) | 2003-11-08 | 2010-03-26 | Prothera Biolog | Preparation and composition of inter-alpha inhibitor proteins from human plasma for therapeutic use |
DE102004001607A1 (de) * | 2004-01-09 | 2005-08-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Arzneimittelkombinationen auf der Basis von Scopin- oder Tropensäureestern mit EGFR-Kinase-Hemmern |
GEP20084551B (en) | 2004-05-06 | 2008-11-25 | Warner Lambert Co | 4-phenylamino-quinazolin-6-yl-amides |
US20060032853A1 (en) * | 2004-07-27 | 2006-02-16 | Freeman Jimmy L | Pressure vessel door |
US20060088533A1 (en) * | 2004-10-08 | 2006-04-27 | Charalabos Pothoulakis | Methods of treating inflammatory bowel disease |
CA2592900A1 (en) | 2005-01-03 | 2006-07-13 | Myriad Genetics Inc. | Nitrogen containing bicyclic compounds and therapeutical use thereof |
US8258145B2 (en) | 2005-01-03 | 2012-09-04 | Myrexis, Inc. | Method of treating brain cancer |
DOP2006000016A (es) * | 2005-01-26 | 2006-07-31 | Aventis Pharma Inc | 2-fenil-indoles como antagonistas del receptor de la prostaglandina d2. |
AU2006210175A1 (en) * | 2005-02-04 | 2006-08-10 | Boehringer Ingelheim International Gmbh | Use of tyrosine kinase inhibitors for the treatment of chronic rhinosinusitis |
EP1856095B1 (en) * | 2005-02-26 | 2011-08-24 | AstraZeneca AB | Quinazoline derivatives as tyrosine kinase inhibitors |
KR100832593B1 (ko) * | 2005-11-08 | 2008-05-27 | 한미약품 주식회사 | 신호전달 저해제로서의 퀴나졸린 유도체 및 이의 제조방법 |
US8404697B2 (en) | 2005-11-11 | 2013-03-26 | Boehringer Ingelheim International Gmbh | Quinazoline derivatives for the treatment of cancer diseases |
CA2663599A1 (en) * | 2006-09-18 | 2008-03-27 | Boehringer Ingelheim International Gmbh | Method for treating cancer harboring egfr mutations |
EP1921070A1 (de) * | 2006-11-10 | 2008-05-14 | Boehringer Ingelheim Pharma GmbH & Co. KG | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstelllung |
MX2009007610A (es) * | 2007-02-06 | 2009-07-24 | Boehringer Ingelheim Int | Heterociclicos biciclicos, medicamentos que contienen estos compuestos, su utilizacion y procedimientos para su preparacion. |
DK2245026T3 (da) * | 2008-02-07 | 2012-10-15 | Boehringer Ingelheim Int | Spirocycliske heterocycler, lægemiddel indeholdende disse forbindelser, deres anvendelse og fremgangsmåde til deres fremstilling |
EP2303276B1 (en) | 2008-05-13 | 2013-11-13 | AstraZeneca AB | Fumarate salt of 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(n-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline |
CA2726281C (en) | 2008-05-28 | 2023-04-18 | Prothera Biologics, Llc | Preparation and composition of inter-alpha inhibitor proteins from blood |
US8426430B2 (en) | 2008-06-30 | 2013-04-23 | Hutchison Medipharma Enterprises Limited | Quinazoline derivatives |
JP5539351B2 (ja) * | 2008-08-08 | 2014-07-02 | 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 | シクロヘキシルオキシ置換ヘテロ環、これらの化合物を含有する医薬、およびそれらを生成するための方法 |
WO2010054285A2 (en) | 2008-11-10 | 2010-05-14 | National Health Research Institutes | Fused bicyclic and tricyclic pyrimidine compounds as tyrosine kinase inhibitors |
US20110236381A1 (en) * | 2008-12-10 | 2011-09-29 | Stavros Garantziotis | Inhibition of inter-alpha trypsin inhibitor for the treatment of airway disease |
EA019959B1 (ru) | 2009-01-16 | 2014-07-30 | Экселиксис, Инк. | Малатная соль n-(4-{[6,7-бис-(метилокси)хинолин-4-ил]окси}фенил)-n'-(4-фторфенил)циклопропан-1,1-дикарбоксамида и ее кристаллические формы для лечения рака |
DK2451445T3 (da) | 2009-07-06 | 2019-06-24 | Boehringer Ingelheim Int | Fremgangsmåde til at tørre bibw2992, dets salte og faste farmaceutiske formuleringer omfattende denne aktive ingrediens |
UA108618C2 (uk) | 2009-08-07 | 2015-05-25 | Застосування c-met-модуляторів в комбінації з темозоломідом та/або променевою терапією для лікування раку | |
TWI406853B (zh) * | 2010-04-07 | 2013-09-01 | Dev Center Biotechnology | Egfr與vegfr-2雙重抑制劑及其用途與製法 |
AU2013312215C1 (en) | 2012-09-09 | 2018-09-06 | Prothera Biologics, Inc. | Treatment of disease using inter-alpha inhibitor proteins |
US9242965B2 (en) | 2013-12-31 | 2016-01-26 | Boehringer Ingelheim International Gmbh | Process for the manufacture of (E)-4-N,N-dialkylamino crotonic acid in HX salt form and use thereof for synthesis of EGFR tyrosine kinase inhibitors |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9508538D0 (en) * | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
EA004316B1 (ru) * | 1998-08-18 | 2004-02-26 | Дзе Реджентс Ов Дзе Юниверсити Ов Калифорния | Способ лечения гиперсекреции слизи |
DE19911509A1 (de) * | 1999-03-15 | 2000-09-21 | Boehringer Ingelheim Pharma | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
UA71976C2 (en) * | 1999-06-21 | 2005-01-17 | Boehringer Ingelheim Pharma | Bicyclic heterocycles and a medicament based thereon |
US20060063752A1 (en) * | 2000-03-14 | 2006-03-23 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them |
US6627634B2 (en) * | 2000-04-08 | 2003-09-30 | Boehringer Ingelheim Pharma Kg | Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them |
US6617329B2 (en) * | 2000-08-26 | 2003-09-09 | Boehringer Ingelheim Pharma Kg | Aminoquinazolines and their use as medicaments |
US6656946B2 (en) * | 2000-08-26 | 2003-12-02 | Boehringer Ingelheim Pharma Kg | Aminoquinazolines which inhibit signal transduction mediated by tyrosine kinases |
US7019012B2 (en) * | 2000-12-20 | 2006-03-28 | Boehringer Ingelheim International Pharma Gmbh & Co. Kg | Quinazoline derivatives and pharmaceutical compositions containing them |
DE10063435A1 (de) * | 2000-12-20 | 2002-07-04 | Boehringer Ingelheim Pharma | Chinazolinderviate,diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
US6924285B2 (en) * | 2002-03-30 | 2005-08-02 | Boehringer Ingelheim Pharma Gmbh & Co. | Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them |
US20040044014A1 (en) * | 2002-04-19 | 2004-03-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for the preparation thereof |
DE10326186A1 (de) * | 2003-06-06 | 2004-12-23 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
US20050059661A1 (en) * | 2003-07-28 | 2005-03-17 | Boehringer Ingelheim International Gmbh | Use of tyrosine kinase inhibitors for the treatment of inflammatory processes |
-
2002
- 2002-02-05 DE DE10204462A patent/DE10204462A1/de not_active Withdrawn
-
2003
- 2003-01-28 CA CA2472293A patent/CA2472293C/en not_active Expired - Fee Related
- 2003-01-28 WO PCT/EP2003/000814 patent/WO2003066060A2/de not_active Application Discontinuation
- 2003-01-28 EP EP03704477A patent/EP1474149A2/de not_active Withdrawn
- 2003-01-28 JP JP2003565484A patent/JP2005525328A/ja active Pending
- 2003-01-28 AU AU2003206785A patent/AU2003206785A1/en not_active Abandoned
- 2003-01-29 US US10/353,616 patent/US20030149062A1/en not_active Abandoned
- 2003-01-30 TW TW092102201A patent/TW200404547A/zh unknown
- 2003-02-03 PE PE2003000121A patent/PE20030866A1/es not_active Application Discontinuation
- 2003-02-04 UY UY27647A patent/UY27647A1/es not_active Application Discontinuation
- 2003-02-05 AR ARP030100362A patent/AR038392A1/es not_active Withdrawn
-
2009
- 2009-08-19 US US12/543,984 patent/US20090306072A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
EP1474149A2 (de) | 2004-11-10 |
US20030149062A1 (en) | 2003-08-07 |
TW200404547A (en) | 2004-04-01 |
WO2003066060A2 (de) | 2003-08-14 |
AU2003206785A1 (en) | 2003-09-02 |
WO2003066060A3 (de) | 2004-01-15 |
CA2472293C (en) | 2011-08-30 |
AR038392A1 (es) | 2005-01-12 |
US20090306072A1 (en) | 2009-12-10 |
DE10204462A1 (de) | 2003-08-07 |
CA2472293A1 (en) | 2003-08-14 |
UY27647A1 (es) | 2003-08-29 |
JP2005525328A (ja) | 2005-08-25 |
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