GB2200115B - Novel peptide derivatives, their production and use - Google Patents

Novel peptide derivatives, their production and use

Info

Publication number
GB2200115B
GB2200115B GB8801040A GB8801040A GB2200115B GB 2200115 B GB2200115 B GB 2200115B GB 8801040 A GB8801040 A GB 8801040A GB 8801040 A GB8801040 A GB 8801040A GB 2200115 B GB2200115 B GB 2200115B
Authority
GB
United Kingdom
Prior art keywords
production
peptide derivatives
novel peptide
novel
derivatives
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
GB8801040A
Other languages
English (en)
Other versions
GB2200115A (en
GB8801040D0 (en
Inventor
Alexander Hagenbach
Rainer Metternich
Emil Pfenniger
Beat Weidmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sandoz AG
Original Assignee
Sandoz AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sandoz AG filed Critical Sandoz AG
Publication of GB8801040D0 publication Critical patent/GB8801040D0/en
Publication of GB2200115A publication Critical patent/GB2200115A/en
Application granted granted Critical
Publication of GB2200115B publication Critical patent/GB2200115B/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/12Antihypertensives
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0227Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the (partial) peptide sequence -Phe-His-NH-(X)2-C(=0)-, e.g. Renin-inhibitors with n = 2 - 6; for n > 6 see C07K5/06 - C07K5/10
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • C07K5/06008Dipeptides with the first amino acid being neutral
    • C07K5/06078Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • C07K5/06191Dipeptides containing heteroatoms different from O, S, or N
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
GB8801040A 1987-01-21 1988-01-18 Novel peptide derivatives, their production and use Expired - Lifetime GB2200115B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3701526 1987-01-21
DE3707339 1987-03-07

Publications (3)

Publication Number Publication Date
GB8801040D0 GB8801040D0 (en) 1988-02-17
GB2200115A GB2200115A (en) 1988-07-27
GB2200115B true GB2200115B (en) 1990-11-14

Family

ID=25851692

Family Applications (1)

Application Number Title Priority Date Filing Date
GB8801040A Expired - Lifetime GB2200115B (en) 1987-01-21 1988-01-18 Novel peptide derivatives, their production and use

Country Status (13)

Country Link
JP (1) JPS6419053A (US06559137-20030506-C00158.png)
KR (1) KR880009041A (US06559137-20030506-C00158.png)
AU (1) AU1037588A (US06559137-20030506-C00158.png)
BE (1) BE1002212A5 (US06559137-20030506-C00158.png)
CH (1) CH676988A5 (US06559137-20030506-C00158.png)
DK (1) DK22588A (US06559137-20030506-C00158.png)
FR (1) FR2609716A1 (US06559137-20030506-C00158.png)
GB (1) GB2200115B (US06559137-20030506-C00158.png)
IL (1) IL85136A0 (US06559137-20030506-C00158.png)
IT (1) IT1219811B (US06559137-20030506-C00158.png)
MY (1) MY102311A (US06559137-20030506-C00158.png)
NL (1) NL8800100A (US06559137-20030506-C00158.png)
SE (1) SE8800169L (US06559137-20030506-C00158.png)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6538006B1 (en) 1998-07-08 2003-03-25 Pharmacia Corporation Retroviral protease inhibitors
USRE43596E1 (en) 1992-08-25 2012-08-21 G.D. Searle Llc α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors

Families Citing this family (71)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6878728B1 (en) 1999-06-11 2005-04-12 Vertex Pharmaceutical Incorporated Inhibitors of aspartyl protease
US20040122000A1 (en) 1981-01-07 2004-06-24 Vertex Pharmaceuticals Incorporated. Inhibitors of aspartyl protease
DE3732971A1 (de) * 1987-09-30 1989-04-20 Hoechst Ag Renin-hemmende dipeptide, verfahren zu deren herstellung, diese enthaltende mittel und ihre verwendung
DE3733296A1 (de) * 1987-10-02 1989-04-20 Merck Patent Gmbh Aminosaeurederivate
EP0329295A1 (en) * 1988-02-01 1989-08-23 The Upjohn Company Renin inhibiting peptides with polar end groups
JP2524814B2 (ja) * 1988-08-25 1996-08-14 キッセイ薬品工業株式会社 α―ヒドロキシ―β―アミノ酸の製造方法
CA2010531A1 (en) * 1989-03-06 1990-09-06 Werner Neidhart Amino acid derivatives
US5185284A (en) * 1989-05-22 1993-02-09 Mitsubishi Denki Kabushiki Kaisha Method of making a semiconductor memory device
US5098924A (en) * 1989-09-15 1992-03-24 E. R. Squibb & Sons, Inc. Diol sulfonamide and sulfinyl renin inhibitors
TW225540B (US06559137-20030506-C00158.png) * 1990-06-28 1994-06-21 Shionogi & Co
US5614522A (en) * 1990-11-19 1997-03-25 G.D. Searle & Co. Retroviral protease inhibitors
US5510487A (en) * 1990-11-19 1996-04-23 G.D. Searle & Co. Retroviral protease inhibitors
HU9301446D0 (en) * 1990-11-19 1993-11-29 Monsanto Co Inhibitors or fetrovirus protease
EP0558603B1 (en) * 1990-11-19 1998-08-26 Monsanto Company Retroviral protease inhibitors
US5475027A (en) * 1990-11-19 1995-12-12 G.D. Searle & Co. Retroviral protease inhibitors
US5482947A (en) * 1990-11-19 1996-01-09 Talley; John J. Retroviral protease inhibitors
ES2151618T3 (es) 1990-11-19 2001-01-01 Monsanto Co Inhibidores de proteasas retrovirales.
US5475013A (en) * 1990-11-19 1995-12-12 Monsanto Company Retroviral protease inhibitors
CA2131182C (en) * 1992-05-20 2005-04-26 John S. Ng Method for making intermediates useful in synthesis of retroviral protease inhibitors
ATE199545T1 (de) 1992-05-21 2001-03-15 Monsanto Co Inhibitoren retroviraler proteasen
AU669223B2 (en) * 1992-08-25 1996-05-30 G.D. Searle & Co. Sulfonylalkanoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US6743929B1 (en) 1992-08-25 2004-06-01 G. D. Searle & Co. Sulfonylalkanoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US6022994A (en) 1992-08-25 2000-02-08 G. D. Searle &. Co. Succinoylamino hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US5968942A (en) * 1992-08-25 1999-10-19 G. D. Searle & Co. α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US7141609B2 (en) 1992-08-25 2006-11-28 G.D. Searle & Co. α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
KR100296461B1 (ko) * 1992-08-25 2001-11-14 죤 에이치. 뷰센 레트로바이러스프로테아제저해제로서유용한n-(알카노일아미노-2-히드록시프로필)-술폰아미드
US6046190A (en) * 1992-08-25 2000-04-04 G.D. Searle & Co. Hydroxyethylamino sulphonamides useful as retroviral protease inhibitors
US5830897A (en) * 1992-08-27 1998-11-03 G. D. Searle & Co. α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
IS2334B (is) * 1992-09-08 2008-02-15 Vertex Pharmaceuticals Inc., (A Massachusetts Corporation) Aspartyl próteasi hemjari af nýjum flokki súlfonamíða
US5723490A (en) * 1992-09-08 1998-03-03 Vertex Pharmaceuticals Incorporated THF-containing sulfonamide inhibitors of aspartyl protease
US5783701A (en) * 1992-09-08 1998-07-21 Vertex Pharmaceuticals, Incorporated Sulfonamide inhibitors of aspartyl protease
US6337398B1 (en) 1992-10-30 2002-01-08 G.D. Searle & Co. Succinoylamino hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors
EP0666843B1 (en) * 1992-10-30 1999-08-18 G.D. Searle & Co. Sulfonylalkanoylamino hydroxyethylamino sulfamic acids useful as retroviral protease inhibitors
DK0666841T3 (da) * 1992-10-30 1997-02-10 Searle & Co Succinoylamino-hydroxyethylaminosulfaminsyrederivater til anvendelse som inhibitorer af retrovirale proteaser
US5578606A (en) 1992-10-30 1996-11-26 G. D. Searle & Co. α- and β-amino acid hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors
US5756498A (en) * 1992-10-30 1998-05-26 G.D. Searle & Co. Sulfonylalkanoylamino hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors
US6156768A (en) 1992-10-30 2000-12-05 G. D. Searle & Co. Alpha- and beta-amino acid hydroxyethylamino sulfamic acid derivatives useful as retroviral protease inhibitors
US5514801A (en) 1992-12-29 1996-05-07 Monsanto Company Cyclic sulfone containing retroviral protease inhibitors
US5830888A (en) * 1993-04-16 1998-11-03 Monsanto Company Macrocyclic retroviral protease inhibitors
US5750648A (en) * 1993-08-20 1998-05-12 G.D. Searle & Co. Retroviral protease inhibitors and combinations thereof
US5602119A (en) * 1993-10-29 1997-02-11 Vazquez; Michael L. Succinoylamino hydroxyethylamino sulfamic acid derivatives useful as retroviral protease inhibitors
US6133444A (en) * 1993-12-22 2000-10-17 Perseptive Biosystems, Inc. Synthons for the synthesis and deprotection of peptide nucleic acids under mild conditions
DE69512220T2 (de) * 1994-03-07 2000-03-16 Vertex Pharmaceuticals Inc. Sulfonamidderivate als aspartylprotease-inhibitoren
ATE201197T1 (de) * 1994-07-07 2001-06-15 Pharmeco Lab Inc Diarinopropanole abgeleitet von aminosäuren
EP1059285A3 (en) * 1994-07-07 2001-10-31 Pharm-Eco Laboratories, Inc. Process for the preparation of 1,3-diamino-2-propanol and 1,3-diamino-2-propanone derivatives
US5475138A (en) * 1994-07-07 1995-12-12 Pharm-Eco Laboratories Incorporated Method preparing amino acid-derived diaminopropanols
US5831117A (en) * 1995-01-20 1998-11-03 G. D. Searle & Co. Method of preparing retroviral protease inhibitor intermediates
JP4014220B2 (ja) 1995-01-20 2007-11-28 ジー.ディー.サール アンド カンパニー ビス−スルホンアミドヒドロキシエチルアミノ レトロ ウイルスプロテアーゼインヒビター
US6140505A (en) 1995-03-10 2000-10-31 G. D. Searle & Co. Synthesis of benzo fused heterocyclic sulfonyl chlorides
US5756533A (en) * 1995-03-10 1998-05-26 G.D. Searle & Co. Amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
RU2174519C2 (ru) 1995-03-10 2001-10-10 Джи. Ди. Сирл Энд Ко. Гидроксиэтиламино сульфонамиды гетероциклокарбонил аминокислоты, ингибирующие ретровирусную протеазу
US6169085B1 (en) 1995-03-10 2001-01-02 G. D. Searle & Company Sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors
EP1188766A1 (en) 1995-03-10 2002-03-20 G.D. Searle & Co. Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US6407134B1 (en) 1995-03-10 2002-06-18 G. D. Searle & Co. Heterocyclecarbonyl amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US6150556A (en) * 1995-03-10 2000-11-21 G. D. Dearle & Co. Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US7339078B2 (en) 1995-03-10 2008-03-04 G.D. Searle Llc Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US6861539B1 (en) 1995-03-10 2005-03-01 G. D. Searle & Co. Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US5705500A (en) * 1995-03-10 1998-01-06 G.D. Searle & Co. Sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors
US5985870A (en) * 1995-03-10 1999-11-16 G.D. Searle & Co. Sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors
US6667307B2 (en) 1997-12-19 2003-12-23 G.D. Searle & Co. Sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors
US5776971A (en) 1995-03-10 1998-07-07 G.D. Searle & Co. Heterocyclecarbonyl amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
US5691372A (en) * 1995-04-19 1997-11-25 Vertex Pharmaceuticals Incorporated Oxygenated-Heterocycle containing sulfonamide inhibitors of aspartyl protease
US6004957A (en) * 1995-06-07 1999-12-21 Vertex Pharmaceuticals, Incorporated Sulfonamide inhibitors of aspartyl protease
US6063963A (en) * 1995-07-05 2000-05-16 Pharm-Eco Laboratories, Inc. Amino acid-derived diaminopropanols
WO1997018205A1 (en) * 1995-11-15 1997-05-22 G.D. Searle & Co. Substituted sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors
US6436989B1 (en) 1997-12-24 2002-08-20 Vertex Pharmaceuticals, Incorporated Prodrugs of aspartyl protease inhibitors
JPH11324710A (ja) 1998-05-20 1999-11-26 Hitachi Ltd ガスタービン発電プラント
DK1086076T3 (da) 1998-06-19 2005-03-29 Vertex Pharma Sulfonamidinhibitorer af aspartylprotease
US6455734B1 (en) 2000-08-09 2002-09-24 Magnesium Diagnostics, Inc. Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states
JP3888095B2 (ja) 2001-07-26 2007-02-28 株式会社日立製作所 ガスタービン設備
US7251926B2 (en) 2001-07-26 2007-08-07 Hitachi, Ltd. Gas turbine installation

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0081783B1 (en) * 1981-12-10 1985-06-19 Merck & Co. Inc. Renin inhibitory peptides having phe 13 deletion
EP0152255A2 (en) * 1984-02-03 1985-08-21 Sankyo Company Limited New renin-inhibitory peptides and their use
EP0163237A2 (en) * 1984-05-29 1985-12-04 Merck & Co. Inc. Di- and tri-peptidal renin inhibitors
EP0184550A2 (de) * 1984-11-13 1986-06-11 Ciba-Geigy Ag 5-Amino-4-hydroxyvalerylamid-Derivate
EP0184855A2 (en) * 1984-12-14 1986-06-18 Abbott Laboratories Resin inhibiting compounds
EP0228192A2 (en) * 1985-11-29 1987-07-08 Sankyo Company Limited Renin-inhibitory oligopeptides, their preparation and use
DE3601248A1 (de) * 1986-01-17 1987-07-23 Hoechst Ag Substituierte 4-amino-3-hydroxybuttersaeure-derivate, verfahren zu deren herstellung, diese enthaltende mittel und ihre verwendung

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4645759A (en) * 1984-06-22 1987-02-24 Abbott Laboratories Renin inhibiting compounds
EP0173481A3 (en) * 1984-08-06 1988-12-21 The Upjohn Company Peptides

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0081783B1 (en) * 1981-12-10 1985-06-19 Merck & Co. Inc. Renin inhibitory peptides having phe 13 deletion
EP0152255A2 (en) * 1984-02-03 1985-08-21 Sankyo Company Limited New renin-inhibitory peptides and their use
EP0163237A2 (en) * 1984-05-29 1985-12-04 Merck & Co. Inc. Di- and tri-peptidal renin inhibitors
EP0184550A2 (de) * 1984-11-13 1986-06-11 Ciba-Geigy Ag 5-Amino-4-hydroxyvalerylamid-Derivate
EP0184855A2 (en) * 1984-12-14 1986-06-18 Abbott Laboratories Resin inhibiting compounds
EP0228192A2 (en) * 1985-11-29 1987-07-08 Sankyo Company Limited Renin-inhibitory oligopeptides, their preparation and use
DE3601248A1 (de) * 1986-01-17 1987-07-23 Hoechst Ag Substituierte 4-amino-3-hydroxybuttersaeure-derivate, verfahren zu deren herstellung, diese enthaltende mittel und ihre verwendung

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Hypertension 8(6) Part 2 II-2 to II-5 (1986) *
Struct. Funct. Proc. Am. Pept. Sym. 8th, ed. V. J. Hruby andD. H. Rich, pp. 511-20 ( *
Tetrahedron Letters 24(41) 4401-4 (1983) *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE43596E1 (en) 1992-08-25 2012-08-21 G.D. Searle Llc α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
USRE43802E1 (en) 1992-08-25 2012-11-13 G.D. Searle Llc α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
US6538006B1 (en) 1998-07-08 2003-03-25 Pharmacia Corporation Retroviral protease inhibitors

Also Published As

Publication number Publication date
FR2609716A1 (fr) 1988-07-22
GB2200115A (en) 1988-07-27
SE8800169D0 (sv) 1988-01-20
DK22588D0 (da) 1988-01-19
DK22588A (da) 1988-07-22
IL85136A0 (en) 1988-06-30
IT1219811B (it) 1990-05-24
JPS6419053A (en) 1989-01-23
IT8847556A0 (it) 1988-01-21
BE1002212A5 (fr) 1990-10-16
SE8800169L (sv) 1988-07-22
NL8800100A (nl) 1988-08-16
GB8801040D0 (en) 1988-02-17
KR880009041A (ko) 1988-09-13
MY102311A (en) 1992-05-28
AU1037588A (en) 1988-09-01
CH676988A5 (US06559137-20030506-C00158.png) 1991-03-28

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