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WO2005074993A3 - Verfahren zur herstellung von konjugaten aus polysacchariden und polynukleotiden - Google Patents

Verfahren zur herstellung von konjugaten aus polysacchariden und polynukleotiden Download PDF

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Publication number
WO2005074993A3
WO2005074993A3 PCT/EP2005/001252 EP2005001252W WO2005074993A3 WO 2005074993 A3 WO2005074993 A3 WO 2005074993A3 EP 2005001252 W EP2005001252 W EP 2005001252W WO 2005074993 A3 WO2005074993 A3 WO 2005074993A3
Authority
WO
WIPO (PCT)
Prior art keywords
aldonic acid
derivative
polynucleotide
reacted
polynucleotides
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.)
Ceased
Application number
PCT/EP2005/001252
Other languages
English (en)
French (fr)
Other versions
WO2005074993A2 (de
Inventor
Klaus Sommermeyer
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.)
Supramol Parenteral Colloids GmbH
TME Pharma AG
Original Assignee
Noxxon Pharma AG
Supramol Parenteral Colloids GmbH
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 Noxxon Pharma AG, Supramol Parenteral Colloids GmbH filed Critical Noxxon Pharma AG
Priority to CN2005800044579A priority Critical patent/CN1917905B/zh
Priority to AU2005210142A priority patent/AU2005210142A1/en
Priority to CA2555467A priority patent/CA2555467C/en
Priority to KR1020067016012A priority patent/KR101189555B1/ko
Priority to JP2006552525A priority patent/JP5193468B2/ja
Priority to EP05715273A priority patent/EP1713509A2/de
Priority to US10/597,787 priority patent/US20090281296A1/en
Priority to BRPI0507540-8A priority patent/BRPI0507540A/pt
Publication of WO2005074993A2 publication Critical patent/WO2005074993A2/de
Publication of WO2005074993A3 publication Critical patent/WO2005074993A3/de
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • 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)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Saccharide Compounds (AREA)

Abstract

Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung eines Konjugates aus einem Polynukleotid und einem Polysaccharid umfassend die Schritte: a) Bereitstellen einer Aldonsäure des Polysaccharides oder eines Derivates davon; b) Umsetzen der Aldonsäure mit einem Alkohol-Derivat, bevorzugterweise einem Carbonat-Derivat eines Alkohols, zu einem Aldonsäure-Ester, bevorzugterweise zu einem aktivierten Aldonsäure-Ester; und c) Umsetzen des Aldonsäure-Esters mit dem Polynukleotid, wobei das Polynukleotid eine funktionale Amino-Gruppe aufweist, wobei das Umsetzen der Aldonsäure mit dem Alkohol-Derivat in Schritt (b) in einem trockenen aprotischen polaren Lösungsmittel erfolgt.
PCT/EP2005/001252 2004-02-09 2005-02-08 Verfahren zur herstellung von konjugaten aus polysacchariden und polynukleotiden Ceased WO2005074993A2 (de)

Priority Applications (8)

Application Number Priority Date Filing Date Title
CN2005800044579A CN1917905B (zh) 2004-02-09 2005-02-08 从多糖和多核苷酸生产缀合物的方法
AU2005210142A AU2005210142A1 (en) 2004-02-09 2005-02-08 Method for producing conjugates of polysaccharides and polynucleotides
CA2555467A CA2555467C (en) 2004-02-09 2005-02-08 Process for the production of conjugates from polysaccharides and polynucleotides
KR1020067016012A KR101189555B1 (ko) 2004-02-09 2005-02-08 폴리사카라이드 및 폴리뉴클레오티드로부터 접합체를제조하는 방법
JP2006552525A JP5193468B2 (ja) 2004-02-09 2005-02-08 多糖とポリヌクレオチドの複合体を製造する方法
EP05715273A EP1713509A2 (de) 2004-02-09 2005-02-08 Verfahren zur herstellung von konjugaten aus polysacchariden und polynukleotiden
US10/597,787 US20090281296A1 (en) 2004-02-09 2005-02-08 Process for the production of conjugates from polysaccharides and polynucelotides
BRPI0507540-8A BRPI0507540A (pt) 2004-02-09 2005-02-08 processo para a produção de conjugados de polissacarìdeos e polinucleotìdeos

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004006249 2004-02-09
DE102004006249.8 2004-02-09

Publications (2)

Publication Number Publication Date
WO2005074993A2 WO2005074993A2 (de) 2005-08-18
WO2005074993A3 true WO2005074993A3 (de) 2006-04-20

Family

ID=34832566

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2005/001252 Ceased WO2005074993A2 (de) 2004-02-09 2005-02-08 Verfahren zur herstellung von konjugaten aus polysacchariden und polynukleotiden

Country Status (9)

Country Link
US (1) US20090281296A1 (de)
EP (1) EP1713509A2 (de)
JP (2) JP5193468B2 (de)
KR (1) KR101189555B1 (de)
CN (1) CN1917905B (de)
AU (1) AU2005210142A1 (de)
BR (1) BRPI0507540A (de)
CA (1) CA2555467C (de)
WO (1) WO2005074993A2 (de)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7538092B2 (en) 2002-10-08 2009-05-26 Fresenius Kabi Deutschland Gmbh Pharmaceutically active oligosaccharide conjugates
US7541328B2 (en) 2002-03-06 2009-06-02 Fresenius Kabi Deutschland Gmbh Coupling proteins to a modified polysaccharide
US8840879B2 (en) 2004-03-11 2014-09-23 Fresenius Kabi Deutschland Gmbh Conjugates of hydroxyalkyl starch and a protein

Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005092391A2 (en) * 2004-03-11 2005-10-06 Fresenius Kabi Deutschland Gmbh Conjugates of hydroxyalkyl starch and a protein
EP2365080B1 (de) 2006-02-14 2016-04-13 NOXXON Pharma AG MCP-1-bindende Nukleinsäuren
EP2407558A1 (de) 2006-10-31 2012-01-18 Noxxon Pharma AG Verfahren zum Nachweis eines einzel- oder doppelsträngigen Nukleinsäuremoleküls
EP2205734A2 (de) 2007-09-24 2010-07-14 Noxxon Pharma AG AN C5a BINDENDE NUKLEINSÄUREN
WO2010108657A2 (en) 2009-03-23 2010-09-30 Noxxon Pharma Ag C5a binding nucleic acids and the use thereof
WO2011131371A1 (en) 2010-04-21 2011-10-27 Noxxon Pharma Ag Lipid binding nucleic acids
WO2012025251A1 (en) 2010-08-27 2012-03-01 Noxxon Pharma Ag Nucleic acids for treatment of chronic complications of diabetes
JP2014503187A (ja) 2010-10-29 2014-02-13 ノクソン ファーマ エージー 身体からヘプシジンを除去するためのヘプシジン結合核酸の使用
KR20140026357A (ko) 2011-01-10 2014-03-05 녹손 파르마 아게 목표 분자에 결합력을 갖는 핵산 및 이를 제조하는 방법
AU2012325233A1 (en) 2011-10-21 2014-04-24 Noxxon Pharma Ag Glucagon binding nucleic acids
CN104136612A (zh) 2012-01-10 2014-11-05 诺松制药股份公司 特异性结合cgrp的核酸
ES2786007T3 (es) 2012-01-10 2020-10-08 Aptarion Biotech Ag Nuevos ácidos nucleicos de unión a C5a
WO2013113503A1 (en) 2012-01-31 2013-08-08 Fresenius Kabi Deutschland Gmbh Conjugates of hydroxyalkyl starch and an oligonucleotide
EP3228715B1 (de) * 2012-02-09 2019-08-14 Life Technologies Corporation Konjugiertes polymerteilchen und herstellungsverfahren dafür
EP2850192B1 (de) 2012-05-16 2023-11-01 APTARION biotech AG Enzymatische synthese von l-nukleinsäuren
JP2017502075A (ja) 2013-11-04 2017-01-19 ノクソン ファーマ エージー 腎障害治療の手段および方法
WO2017004559A1 (en) 2015-07-02 2017-01-05 Life Technologies Corporation Conjugation of carboxyl functional hydrophilic beads
EP3320115B1 (de) 2015-07-06 2020-09-02 Life Technologies Corporation Substrat und verfahren zur sequenzierung
EP3443095A1 (de) 2016-04-15 2019-02-20 Noxxon Pharma AG Verfahren zur modulation der anzahl und der verteilung von tumorinfiltrierenden leukozyten bei tumoren
KR20250025627A (ko) 2022-06-21 2025-02-24 티엠이 파마 아게 대상체의 종양을 치료하는 방법
EP4306640A1 (de) 2022-06-21 2024-01-17 TME Pharma AG Verfahren zur behandlung eines tumors in einem patienten
WO2025196240A1 (en) 2024-03-20 2025-09-25 Aptarion Biotech Ag Method of treating a disorder with a c5a inhibitor
EP4620474A1 (de) 2024-03-20 2025-09-24 APTARION biotech AG Verfahren zur behandlung einer erkrankung mit einem c5a-hemmer

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3720663A (en) * 1971-06-24 1973-03-13 Nat Starch Chem Corp Preparation of starch esters
WO1994001448A1 (en) * 1992-07-06 1994-01-20 Pharmagenics, Inc. Oligonucleotides modified with conjugate groups
WO1997021452A2 (en) * 1995-12-14 1997-06-19 Advanced Magnetics, Inc. Macromolecular prodrugs of nucleotide analogs
WO2002080979A2 (de) * 2001-03-16 2002-10-17 Fresenius Kabi Deutschland Gmbh Hydroxyalkylstärke-wirkstoff-konjugate
WO2003070772A1 (de) * 2002-02-20 2003-08-28 Fresenius Kabi Deutschland Gmbh Stärkederivate, stärke-wirkstoff-konjugate, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
DE10254745A1 (de) * 2002-11-23 2004-06-03 Supramol Parenteral Colloids Gmbh Imidazolide von Polysaccharid Aldonsäuren, Verfahren zu ihrer Herstellung und Verwendung zur Kopplung an pharmazeutische Wirkstoffe
WO2004050710A2 (de) * 2002-12-04 2004-06-17 Supramol Parenteral Colloids Gmbh Aldonsäure-ester, verfahren zu ihrer herstellung und verfahren zur herstellung von mit polysacchariden oder polysaccharid-derivaten an freien aminogruppen gekoppelten pharmazeutischen wirkstoffen
DE10302520A1 (de) * 2003-01-23 2004-08-05 Supramol Parenteral Colloids Gmbh Kohlensäurediester von Stärkefraktionen und deren Derivate, Verfahren zu ihrer Herstellung und Verwendung zur Kopplung an pharmazeutische Wirkstoffe

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2809112B1 (fr) * 2000-05-16 2004-05-07 Centre Nat Rech Scient Materiaux a base de polymeres biodegradables et son procede de preparation
ATE308589T1 (de) * 2000-05-23 2005-11-15 Dyomics Gmbh Stabile nir-marker-farbstoffe auf der basis von benzopyrylium-polymethinen
ES2629615T3 (es) * 2001-10-26 2017-08-11 Noxxon Pharma Ag Ácido L-nucleico modificado
DE10209821A1 (de) * 2002-03-06 2003-09-25 Biotechnologie Ges Mittelhesse Kopplung von Proteinen an ein modifiziertes Polysaccharid

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3720663A (en) * 1971-06-24 1973-03-13 Nat Starch Chem Corp Preparation of starch esters
WO1994001448A1 (en) * 1992-07-06 1994-01-20 Pharmagenics, Inc. Oligonucleotides modified with conjugate groups
WO1997021452A2 (en) * 1995-12-14 1997-06-19 Advanced Magnetics, Inc. Macromolecular prodrugs of nucleotide analogs
WO2002080979A2 (de) * 2001-03-16 2002-10-17 Fresenius Kabi Deutschland Gmbh Hydroxyalkylstärke-wirkstoff-konjugate
WO2003070772A1 (de) * 2002-02-20 2003-08-28 Fresenius Kabi Deutschland Gmbh Stärkederivate, stärke-wirkstoff-konjugate, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
DE10254745A1 (de) * 2002-11-23 2004-06-03 Supramol Parenteral Colloids Gmbh Imidazolide von Polysaccharid Aldonsäuren, Verfahren zu ihrer Herstellung und Verwendung zur Kopplung an pharmazeutische Wirkstoffe
WO2004050710A2 (de) * 2002-12-04 2004-06-17 Supramol Parenteral Colloids Gmbh Aldonsäure-ester, verfahren zu ihrer herstellung und verfahren zur herstellung von mit polysacchariden oder polysaccharid-derivaten an freien aminogruppen gekoppelten pharmazeutischen wirkstoffen
DE10302520A1 (de) * 2003-01-23 2004-08-05 Supramol Parenteral Colloids Gmbh Kohlensäurediester von Stärkefraktionen und deren Derivate, Verfahren zu ihrer Herstellung und Verwendung zur Kopplung an pharmazeutische Wirkstoffe

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HAGINAKA J ET AL: "Separation of enantiomers on a chiral stationary phase based on ovoglycoprotein - I. Influences of the pore size of base silica materials and bound protein amounts on chiral resolution", JOURNAL OF CHROMATOGRAPHY A, ELSEVIER, AMSTERDAM, NL, vol. 773, no. 1-2, 27 June 1997 (1997-06-27), pages 85 - 91, XP004125495, ISSN: 0021-9673 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7541328B2 (en) 2002-03-06 2009-06-02 Fresenius Kabi Deutschland Gmbh Coupling proteins to a modified polysaccharide
US8916518B2 (en) 2002-03-06 2014-12-23 Fresenius Kabi Deutschland Gmbh Coupling proteins to a modified polysaccharide
US7538092B2 (en) 2002-10-08 2009-05-26 Fresenius Kabi Deutschland Gmbh Pharmaceutically active oligosaccharide conjugates
US8840879B2 (en) 2004-03-11 2014-09-23 Fresenius Kabi Deutschland Gmbh Conjugates of hydroxyalkyl starch and a protein

Also Published As

Publication number Publication date
US20090281296A1 (en) 2009-11-12
CN1917905B (zh) 2012-01-04
JP2013056889A (ja) 2013-03-28
BRPI0507540A (pt) 2007-07-03
AU2005210142A1 (en) 2005-08-18
WO2005074993A2 (de) 2005-08-18
JP5193468B2 (ja) 2013-05-08
KR20060132906A (ko) 2006-12-22
CA2555467C (en) 2012-10-09
EP1713509A2 (de) 2006-10-25
JP2007522164A (ja) 2007-08-09
KR101189555B1 (ko) 2012-10-16
CA2555467A1 (en) 2005-08-18
CN1917905A (zh) 2007-02-21

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