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WO2002000576A1 - Procede pour transferer des groupes alkylidene sur des composes organiques - Google Patents

Procede pour transferer des groupes alkylidene sur des composes organiques Download PDF

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Publication number
WO2002000576A1
WO2002000576A1 PCT/EP2001/005541 EP0105541W WO0200576A1 WO 2002000576 A1 WO2002000576 A1 WO 2002000576A1 EP 0105541 W EP0105541 W EP 0105541W WO 0200576 A1 WO0200576 A1 WO 0200576A1
Authority
WO
WIPO (PCT)
Prior art keywords
microreactor
organic
compound
alkylidene group
group transfer
Prior art date
Application number
PCT/EP2001/005541
Other languages
German (de)
English (en)
Inventor
Hanns Wurziger
Guido Pieper
Norbert Schwesinger
Original Assignee
Merck Patent 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 Merck Patent Gmbh filed Critical Merck Patent Gmbh
Priority to JP2002505327A priority Critical patent/JP2004501879A/ja
Priority to EP01933970A priority patent/EP1296915A1/fr
Priority to AU2001260303A priority patent/AU2001260303A1/en
Publication of WO2002000576A1 publication Critical patent/WO2002000576A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
    • C07C1/20—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from organic compounds containing only oxygen atoms as heteroatoms
    • C07C1/207—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from organic compounds containing only oxygen atoms as heteroatoms from carbonyl compounds
    • C07C1/2072—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from organic compounds containing only oxygen atoms as heteroatoms from carbonyl compounds by condensation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/0095—Control aspects
    • B01J2219/00984—Residence time

Definitions

  • the present invention relates to a method for transferring alkylidene groups to organic compounds.
  • the object of the present invention is therefore to provide a process for transferring alkylidene groups to organic compounds which avoids the disadvantages mentioned above.
  • This process should in particular be able to be carried out in a simple, reproducible manner with increased safety for humans and the environment and with good yields, and the reaction conditions should be very easy to control.
  • This object is surprisingly achieved by the process according to the invention for transferring alkylidene groups to organic compounds, in which at least one organic compound in liquid or dissolved form is mixed with at least one alkylidene group transfer reagent in liquid or dissolved form in at least one microreactor , reacts during a residence time and the olefin thus obtained is optionally isolated from the reaction mixture.
  • individual organic compounds or mixtures of at least two of these compounds can be reacted by the process claimed. Only one organic compound is preferably reacted in each case in the process according to the invention.
  • a microreactor in the sense of the invention is a reactor with a volume ⁇ 1000 ⁇ l in which the liquids and / or solutions are intimately mixed at least once.
  • the volume of the microreactor is preferably ⁇ 100 ⁇ l, particularly preferably ⁇ 50 ⁇ l.
  • the microreactor is preferably produced from thin, interconnected silicon structures.
  • the microreactor is preferably a miniaturized flow reactor, particularly preferably a static micromixer.
  • the microreactor is very particularly preferably a static micromixer, as described in the patent application with the international publication number WO 96/30113, which is hereby introduced as a reference and is considered part of the disclosure.
  • Such a microreactor has small channels in which liquids and / or chemicals are present Compounds are mixed together by the kinetic energy of the flowing liquids and / or solutions.
  • the channels of the microreactor preferably have a diameter of 10 to 1000 ⁇ m, particularly preferably 20 to 800 ⁇ m and very particularly preferably 30 to 400 ⁇ m.
  • the liquids and / or solutions are preferably pumped into the microreactor in such a way that they flow through it at a flow rate of 0.01 ⁇ l / min to 100 ml / min, particularly preferably 1 ⁇ l / min to 1 ml / min.
  • the microreactor can preferably be tempered.
  • the microreactor is preferably connected via an outlet to at least one retention zone, preferably a capillary, particularly preferably a temperature-controlled capillary.
  • the liquids and / or solutions are passed into this residence zone or capillary after they have been mixed in the microreactor in order to extend their residence time.
  • the residence time in the sense of the invention is the time between the mixing of the starting materials and the working up of the resulting reaction solution for the analysis or isolation of the desired product (s).
  • the required residence time in the process according to the invention depends on various parameters, such as, for example, the temperature or the reactivity of the starting materials. It is possible for the person skilled in the art to adapt the dwell time to these parameters and thus to achieve an optimal reaction course.
  • the residence time of the reaction solution in the system used comprising at least one microreactor and optionally a residence section, can be set by selecting the flow rate of the liquids and / or solutions used.
  • the reaction mixture is likewise preferably passed through two or more microreactors connected in series. The result of this is that the residence time is increased even at an increased flow rate and the components used in the alkylidene group transfer reaction are reacted in such a way that an optimum product yield of the desired olefin (s) is achieved.
  • reaction mixture is passed through two or more microreactors arranged in parallel in order to increase the throughput.
  • the number and the arrangement of the channels in one or more microreactor (s) are varied in such a way that the residence time is increased, so that here too, with an increased flow rate, an optimal yield of the desired olefin (s) is achieved.
  • the residence time of the reaction solution in the microreactor is preferably ⁇ 15 hours, preferably ⁇ 3 hours, particularly preferably ⁇ 1 hour.
  • the process according to the invention can be carried out in a very wide temperature range, which is essentially due to the temperature resistance of the materials used for the construction of the microreactor, if appropriate the residence zone, and further constituents, such as, for example, connections and seals, and the physical properties Properties of the solutions and / or liquids used is limited.
  • the process according to the invention is preferably carried out at a temperature of from -100 to +100 ° C., preferably from -40 to + 50 ° C., particularly preferably from 0 to +25 ° C.
  • the process according to the invention can be carried out either continuously or batchwise. It is preferably carried out continuously.
  • the course of the reaction of the alkylidene group transfer reaction in the process according to the invention can be followed and, if necessary, regulated using various analytical methods known to the person skilled in the art.
  • the course of the reaction is preferably followed by chromatography, particularly preferably by high-pressure liquid chromatography, and, if necessary, regulated.
  • the control of the reaction is significantly improved compared to known methods.
  • the olefin (s) formed is / are optionally isolated.
  • the olefin (s) formed is / are preferably isolated from the reaction mixture by extraction. All organic compounds known to the person skilled in the art as substrates of alkylidene group transfer reactions can be used as organic compounds in the process according to the invention.
  • the organic compounds are preferably selected from ketones, lactones, carboxylic acid esters, carboxamides or a mixture of at least two of these compounds.
  • ketones known to the person skilled in the art which are suitable as substrates for alkylidene group transfer reactions can be used as ketones. This also includes aliphatic, vinylogenic, aromatic and heteroaromatic ketones.
  • lactones known to the person skilled in the art which are suitable as substrates for alkylidene group transfer reactions can be used as lactones. This also includes aliphatic, vinylogenic, aromatic and heteroaromatic lactones.
  • Carboxylic acid esters are used which are suitable as substrates for alkylidene group transfer reactions. This also includes aliphatic, vinylogenic, aromatic and heteroaromatic carboxylic acid esters.
  • Carboxamides are used which are suitable as substrates for alkylidene group transfer reactions. This also includes aliphatic, vinylogenic, aromatic and heteroaromatic carboxamides.
  • aliphatic ketones, lactones, carboxylic acid esters and carboxylic acid amides are also understood to mean saturated, unsaturated and branched ketones, lactones, carboxylic acid esters and carboxylic acid amides as well as cyclic ketones, carboxylic acid esters and carboxylic acid amides, which may also be substituted.
  • vinylogenic ketones, lactones, carboxylic esters and carboxamides are understood to mean ketones, lactones, carboxylic esters and carboxamides which have a double bond in the ⁇ position to the carbonyl group.
  • aromatic ketones, lactones, carboxylic acid esters and carboxamides also include ketones, lactones, carboxylic esters and carboxamides and / or their derivatives which have a monocyclic and / or polycyclic homoaromatic backbone or a corresponding partial structure, e.g. in the form of substituents.
  • heteroaromatic ketones, lactones, carboxylic esters and carboxamides also include ketones, lactones, carboxylic esters and carboxamides and / or their derivatives which have at least one monocyclic and / or polycyclic heteroaromatic backbone or a corresponding partial structure, e.g. in the form of substituents.
  • These heteroaromatic basic structures or partial structures particularly preferably comprise at least one oxygen and / or nitrogen and / or sulfur atom.
  • alkylidene group transfer reagents in the process according to the invention all known to those skilled in the art for Alkylidene group transfer reactions suitable alkylidene group transfer reagents or a mixture of at least two of these reagents can be used.
  • Alkylidene group transfer reagents for the purposes of the invention also include alkylidene group transfer reagents formed in situ, i.e. Alkylidene group transfer reagents that are formed immediately before or during the alkylidene group transfer reaction.
  • the alkylidene group transfer reagent [(cyclopentadienyl) 2 Ti (CH 2 ) (CI) Al (CH3) 2] (“Tebbe reagent”), a biscyclopentadienyltitanium dialkyl compound, is an alkyl compound
  • Transition metal an alkylidene compound of a transition metal or a mixture of at least two of these compounds.
  • Dimethyltitanocene can preferably be used as the biscyclopentadienyltitanium dialkyl compound.
  • the alkylidene compound of a transition metal which can optionally also be generated in situ, at least one compound of the general formula (I),
  • n an integer from 1 to 9, preferably from 1 to 6, particularly preferably 1 or 2, depending on the ligand (s) L and the transition metal M,
  • radicals R are an organic radical, preferably an optionally substituted alkyl or aryl radical,
  • M is a transition metal, preferably titanium, zirconium or hafnium, particularly preferably titanium
  • radicals L identical or different, an organic or inorganic ligand, preferably a cyclopentandienyl radical or a pentamethylcyclopentadienyl radical
  • alkylidene group transfer reagent is generated in situ, this can preferably be achieved by a mixture of a compound of the general formula R 1 -CH 2 -X, in which R 1 is an organic radical or a halogen radical and X is a halogen -Rest means zinc and titanium tetrachloride, are particularly preferably generated by a mixture of methylene bromide, zinc and titanium tetrachloride.
  • the molar ratio of the alkylidene group transfer agent (s) to the organic compound (s) in the process according to the invention depends on the reactivity of the organic compound (s) used and the reactivity of the alkylidene (s) used.
  • Group transfer reagent (ien) The alkylidene group transfer reagent (s) and the organic compound (s) are preferably used in an equimolar ratio.
  • the alkylidene group transfer reagent (s) is / are used in a 2-fold to 20-fold molar excess, particularly preferably in a 3-fold to 15-fold, very particularly preferably in a 4-fold to 10-fold excess, based on the organic compound (s) used.
  • the selectivity of the reaction itself depends on a number of other parameters, e.g. the concentration of the reagents used, e.g. the temperature, the type of alkylidene group transfer agent used or the residence time. It is possible for the person skilled in the art to adapt the various parameters to the respective reaction in such a way that the desired olefin (s) is (are) obtained.
  • the organic compounds and alkylidene group transfer reagents used are either themselves liquid or are in dissolved form. If either the alkylidene group transfer reagent or the organic compound itself is already liquid, these can optionally also be used as solvents for the respective other reaction component. If these are not already in liquid form, they must be dissolved in a suitable solvent before the process according to the invention is carried out become.
  • Preferred solvents are halogenated solvents, particularly preferably dichloromethane, chloroform, 1, 2-dichloroethane or 1, 1, 2,2-tetrachloroethane, straight-chain, branched or cyclic paraffins, particularly preferably pentane, hexane, heptane, octane, cyclopentane, cyclohexane, Cycloheptane or cyclooctane or straight-chain, branched or cyclic ethers, particularly preferably diethyl ether, methyl tert-butyl ether, tetrahydrofuran or dioxane, aromatic solvents, particularly preferably toluene, xylenes, ligroin or phenyl ether, N-containing heterocyclic solvents, particularly preferably pyridine or N -Methylpyrrolidone, or a mixture of at least two of the solvents mentioned above.
  • the risk to humans and the environment from escaping chemicals is considerably reduced and thus leads to increased safety when handling hazardous substances.
  • the transfer of alkylidene groups to organic compounds by the process according to the invention also enables better control of the reaction conditions, e.g. Reaction time and temperature than is possible in the conventional processes.
  • the risk of explosions in the case of very strongly exothermic alkylidene group transfer reactions is significantly reduced in the process according to the invention.
  • the temperature can be individually selected and kept constant in each volume element of the system.
  • the course of the reaction of the alkylidene group transfer reactions can be regulated very quickly and precisely in the process according to the invention.
  • the olefins can thus be obtained in very good and reproducible yields.
  • the process according to the invention also has the advantage that oxidation-sensitive organic compounds and alkylidene group transfer reagents, which are usually in a protective gas atmosphere must be handled, can be used in the process according to the invention without a protective gas atmosphere.
  • a methylene group was transferred to benzophenone using the Tebbe reagent in a static micromixer (Ilmenau University of Technology, Faculty of Mechanical Engineering, Dr.-Ing. Norbert Schwesinger, P.O.Box 100565, D-98684, Ilmenau) with a size of 40 mm x 25 mm x 1 mm, which had a total of 11 mixing stages with a volume of 0.125 ⁇ l each.
  • the total pressure loss was approximately 1000 Pa.
  • the static micromixer was through an outlet and an omnifit
  • the experimental set-up was calibrated for the dependence of the residence time on the pump flow rate before the reaction was carried out.
  • the dwell time was set to 15 seconds.
  • the reactions were followed using a Merck Hitachi LaChrom HPLC instrument.
  • the benzophenone was completely converted to 1,1-diphenylethylene after just 15 seconds.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé pour transférer des groupes alkylidène sur des composés organiques, selon lequel au moins un composé organique, sous forme liquide ou dissoute, est mélangé et mis à réagir pendant un certain temps avec au moins un réactif de transfert de groupes alkylidène, sous forme liquide ou dissoute, dans au moins un microréacteur. L'oléfine ainsi obtenue peut éventuellement être isolée du mélange de la réaction.
PCT/EP2001/005541 2000-06-28 2001-05-16 Procede pour transferer des groupes alkylidene sur des composes organiques WO2002000576A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2002505327A JP2004501879A (ja) 2000-06-28 2001-05-16 アルキリデン基を有機化合物に転移させるための方法
EP01933970A EP1296915A1 (fr) 2000-06-28 2001-05-16 Procede pour transferer des groupes alkylidene sur des composes organiques
AU2001260303A AU2001260303A1 (en) 2000-06-28 2001-05-16 Method for transferring alkylidene groups to organic compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE2000131380 DE10031380A1 (de) 2000-06-28 2000-06-28 Verfahren zur Übertragung von Alkyliden-Gruppen auf organischen Verbindungen
DE10031380.9 2000-06-28

Publications (1)

Publication Number Publication Date
WO2002000576A1 true WO2002000576A1 (fr) 2002-01-03

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Application Number Title Priority Date Filing Date
PCT/EP2001/005541 WO2002000576A1 (fr) 2000-06-28 2001-05-16 Procede pour transferer des groupes alkylidene sur des composes organiques

Country Status (5)

Country Link
EP (1) EP1296915A1 (fr)
JP (1) JP2004501879A (fr)
AU (1) AU2001260303A1 (fr)
DE (1) DE10031380A1 (fr)
WO (1) WO2002000576A1 (fr)

Cited By (15)

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AT501927A1 (de) * 2005-05-23 2006-12-15 Dsm Fine Chem Austria Gmbh Verfahren zur durchführung von reaktionen unter beteiligung von carbokationen
US7754206B2 (en) 2000-08-03 2010-07-13 The Regents Of The University Of Michigan Method for treating cancer using a Notch4 ligand antagonist
US7919092B2 (en) 2006-06-13 2011-04-05 Oncomed Pharmaceuticals, Inc. Antibodies to notch receptors
US8088617B2 (en) 2007-01-24 2012-01-03 Oncomed Pharmaceuticals, Inc. Antibodies that bind the glutamate ligand binding region of Notch1
US8226943B2 (en) 2008-07-08 2012-07-24 Oncomed Pharmaceuticals, Inc. Antibodies to notch receptors
US8324361B2 (en) 2005-10-31 2012-12-04 Oncomed Pharmaceuticals, Inc. Nucleic acid molecules encoding soluble frizzled (FZD) receptors
US8507442B2 (en) 2008-09-26 2013-08-13 Oncomed Pharmaceuticals, Inc. Methods of use for an antibody against human frizzled receptors 1, 2. 5, 7 or 8
US8551789B2 (en) 2010-04-01 2013-10-08 OncoMed Pharmaceuticals Frizzled-binding agents and their use in screening for WNT inhibitors
US8834875B2 (en) 2010-01-13 2014-09-16 Oncomed Pharmaceuticals, Inc. Notch1 binding agents and methods of use thereof
US9132189B2 (en) 2008-07-08 2015-09-15 Oncomed Pharmaceuticals, Inc. Notch1 binding agents and methods of use thereof
US9157904B2 (en) 2010-01-12 2015-10-13 Oncomed Pharmaceuticals, Inc. Wnt antagonists and methods of treatment and screening
US9168300B2 (en) 2013-03-14 2015-10-27 Oncomed Pharmaceuticals, Inc. MET-binding agents and uses thereof
US9266959B2 (en) 2012-10-23 2016-02-23 Oncomed Pharmaceuticals, Inc. Methods of treating neuroendocrine tumors using frizzled-binding agents
US9359444B2 (en) 2013-02-04 2016-06-07 Oncomed Pharmaceuticals Inc. Methods and monitoring of treatment with a Wnt pathway inhibitor
US9850311B2 (en) 2005-10-31 2017-12-26 Oncomed Pharmaceuticals, Inc. Compositions and methods for diagnosing and treating cancer

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WO2016104755A1 (fr) * 2014-12-25 2016-06-30 旭硝子株式会社 Procédé de production d'un dérivé de dihydropyrazinone

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US9089556B2 (en) 2000-08-03 2015-07-28 The Regents Of The University Of Michigan Method for treating cancer using an antibody that inhibits notch4 signaling
US7754206B2 (en) 2000-08-03 2010-07-13 The Regents Of The University Of Michigan Method for treating cancer using a Notch4 ligand antagonist
US9492538B2 (en) 2000-08-03 2016-11-15 The Regents Of The University Of Michigan Isolation and use of solid tumor stem cells
AT501927B1 (de) * 2005-05-23 2007-06-15 Dsm Fine Chem Austria Gmbh Verbessertes verfahren zur durchführung von ritterreaktionen, elektrophilen additionen an alkenen oder friedel-crafts-alkylierungen
AT501927A1 (de) * 2005-05-23 2006-12-15 Dsm Fine Chem Austria Gmbh Verfahren zur durchführung von reaktionen unter beteiligung von carbokationen
US9732139B2 (en) 2005-10-31 2017-08-15 Oncomed Pharmaceuticals, Inc. Methods of treating cancer by administering a soluble receptor comprising a human Fc domain and the Fri domain from human frizzled receptor
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US8324361B2 (en) 2005-10-31 2012-12-04 Oncomed Pharmaceuticals, Inc. Nucleic acid molecules encoding soluble frizzled (FZD) receptors
US9228013B2 (en) 2005-10-31 2016-01-05 OncoMed Pharmaceuticals Methods of using the FRI domain of human frizzled receptor for inhibiting Wnt signaling in a tumor or tumor cell
US8765913B2 (en) 2005-10-31 2014-07-01 Oncomed Pharmaceuticals, Inc. Human frizzled (FZD) receptor polypeptides and methods of use thereof for treating cancer and inhibiting growth of tumor cells
US8404237B2 (en) 2006-06-13 2013-03-26 OncoMed Pharamaceuticals, Inc. Antibodies to the NOTCH1 receptor
US8784811B2 (en) 2006-06-13 2014-07-22 Oncomed Pharmaceuticals, Inc. Method of treating cancer using antibodies to a non-ligand binding region of NOTCH1
US9676865B2 (en) 2006-06-13 2017-06-13 Oncomed Pharmaceuticals, Inc. Antibodies to a non-ligand binding region of at least two NOTCH receptors
US8206713B2 (en) 2006-06-13 2012-06-26 Oncomed Pharmaceuticals, Inc. Method of treating cancer using antibodies to a non-ligand binding region of NOTCH2
US7919092B2 (en) 2006-06-13 2011-04-05 Oncomed Pharmaceuticals, Inc. Antibodies to notch receptors
US8088617B2 (en) 2007-01-24 2012-01-03 Oncomed Pharmaceuticals, Inc. Antibodies that bind the glutamate ligand binding region of Notch1
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US8921106B2 (en) 2007-01-24 2014-12-30 Oncomed Pharmaceuticals, Inc. Antibodies that bind the glutamate ligand binding region of NOTCH3
US8460661B2 (en) 2007-01-24 2013-06-11 Oncomed Pharmaceuticals, Inc. Methods of using antibodies that bind the glutamate ligand binding region of Notch1
US8945547B2 (en) 2008-07-08 2015-02-03 Oncomed Pharmaceuticals, Inc. Notch1 receptor antibodies and methods of treatment
US8226943B2 (en) 2008-07-08 2012-07-24 Oncomed Pharmaceuticals, Inc. Antibodies to notch receptors
US9499613B2 (en) 2008-07-08 2016-11-22 Oncomed Pharmaceuticals, Inc. Notch1 receptor binding agents and methods of use thereof
US8980260B2 (en) 2008-07-08 2015-03-17 Oncomed Pharmaceuticals, Inc. Monoclonal antibody that binds human notch2 and notch3
US8945874B2 (en) 2008-07-08 2015-02-03 Oncomed Pharmaceuticals, Inc. Polynucleotides encoding NOTCH1 receptor antibodies
US9132189B2 (en) 2008-07-08 2015-09-15 Oncomed Pharmaceuticals, Inc. Notch1 binding agents and methods of use thereof
US8945873B2 (en) 2008-07-08 2015-02-03 Oncomed Pharmaceuticals, Inc. Polynucleotides encoding Notch receptor antibodies
US9505832B2 (en) 2008-07-08 2016-11-29 Oncomed Pharmaceuticals, Inc. Method of treating cancer by administering a monoclonal antibody that binds human NOTCH2 and NOTCH3
US8425903B2 (en) 2008-07-08 2013-04-23 Oncomed Pharmaceuticals, Inc. Methods of treatment by administering antibodies to notch receptors
US8435513B2 (en) 2008-07-08 2013-05-07 Oncomed Pharmaceuticals, Inc. NOTCH1 receptor antibodies and methods of treatment
US9273139B2 (en) 2008-09-26 2016-03-01 Oncomed Pharmaceuticals, Inc. Monoclonal antibodies against frizzled
US8507442B2 (en) 2008-09-26 2013-08-13 Oncomed Pharmaceuticals, Inc. Methods of use for an antibody against human frizzled receptors 1, 2. 5, 7 or 8
US9573998B2 (en) 2008-09-26 2017-02-21 Oncomed Pharmaceuticals, Inc. Antibodies against human FZD5 and FZD8
US8975044B2 (en) 2008-09-26 2015-03-10 Oncomed Pharmaceuticals, Inc. Polynucleotides encoding for frizzled-binding agents and uses thereof
US9157904B2 (en) 2010-01-12 2015-10-13 Oncomed Pharmaceuticals, Inc. Wnt antagonists and methods of treatment and screening
US9579361B2 (en) 2010-01-12 2017-02-28 Oncomed Pharmaceuticals, Inc. Wnt antagonist and methods of treatment and screening
US8834875B2 (en) 2010-01-13 2014-09-16 Oncomed Pharmaceuticals, Inc. Notch1 binding agents and methods of use thereof
US9499630B2 (en) 2010-04-01 2016-11-22 Oncomed Pharmaceuticals, Inc. Frizzled-binding agents and uses thereof
US8551789B2 (en) 2010-04-01 2013-10-08 OncoMed Pharmaceuticals Frizzled-binding agents and their use in screening for WNT inhibitors
US9266959B2 (en) 2012-10-23 2016-02-23 Oncomed Pharmaceuticals, Inc. Methods of treating neuroendocrine tumors using frizzled-binding agents
US9359444B2 (en) 2013-02-04 2016-06-07 Oncomed Pharmaceuticals Inc. Methods and monitoring of treatment with a Wnt pathway inhibitor
US9987357B2 (en) 2013-02-04 2018-06-05 Oncomed Pharmaceuticals, Inc. Methods and monitoring of treatment with a WNT pathway inhibitor
US9168300B2 (en) 2013-03-14 2015-10-27 Oncomed Pharmaceuticals, Inc. MET-binding agents and uses thereof

Also Published As

Publication number Publication date
JP2004501879A (ja) 2004-01-22
DE10031380A1 (de) 2002-01-10
AU2001260303A1 (en) 2002-01-08
EP1296915A1 (fr) 2003-04-02

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