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WO2004005269A1 - Procede de production d'esters thiazol-2-ylmethyliques substitues - Google Patents

Procede de production d'esters thiazol-2-ylmethyliques substitues Download PDF

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Publication number
WO2004005269A1
WO2004005269A1 PCT/EP2003/007414 EP0307414W WO2004005269A1 WO 2004005269 A1 WO2004005269 A1 WO 2004005269A1 EP 0307414 W EP0307414 W EP 0307414W WO 2004005269 A1 WO2004005269 A1 WO 2004005269A1
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group
alkyl
hydrogen atom
heteroalkyl
groups
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PCT/EP2003/007414
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German (de)
English (en)
Inventor
Alexander Doemling
Bernd Henkel
Barbara Beck
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Morphochem Ag Komb Chemie
Alexander Doemling
Bernd Henkel
Barbara Beck
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Application filed by Morphochem Ag Komb Chemie, Alexander Doemling, Bernd Henkel, Barbara Beck filed Critical Morphochem Ag Komb Chemie
Priority to AU2003250014A priority Critical patent/AU2003250014A1/en
Publication of WO2004005269A1 publication Critical patent/WO2004005269A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a new process for the preparation of substituted thiazol-2-ylmethyl esters via a multicomponent reaction. These compounds are of particular interest in the synthesis of tubulysins and tubulysin derivatives.
  • Thiazol-2-methyl esters are found in numerous biologically active natural products as well as synthetic derivatives such as. B. Lyngbyabellin A and B, tubulysins, thiostreptones, myxothiazoles, archazolid A, tallysomycin, bleomycin, dysidenin, dolabellin and synthetic epothilone derivatives (Yokokawa et al. Tetrahedron et al. 2001, 42, 4171-4174; Konishi et al Antibiot 1977, 30, 789-805; Sone et al. J. Org. Chem. 1995, 60, 4774-4781; Kazlauskas et al. Tetrahedron Lett. 1977, 36, 3183-3186) and therefore is simpler and more efficient Access to this class of substances is particularly important in the synthesis of active substances.
  • the object of the present invention was in particular to provide a new one-pot process for the preparation of these compounds, which takes place in a multi-component reaction. Since multicomponent reactions are very variable, they are particularly suitable for the synthesis of substance libraries to find lead structures in the pharmaceutical industry (A. Dömling, I. Ugi, Angew. Chem. 2000, 112, 3300-3344). Another object of the present invention was to use this method to provide an efficient synthesis of the tubulysin class of compounds.
  • the Tubulysins were first developed by the Höfle and
  • Tubulysins (I) are tetrapeptides that contain three unusual amino acids, making their synthesis a challenge for organic synthetic chemistry.
  • R 2 H,
  • R 4 is a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or a heteroaralkyl radical or a group of the formula COO -L-Pol is where L is a linker and Pol is a polymeric support;
  • R 5 is a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or a heteroaralkyl radical;
  • R 6 is a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or a heteroaralkyl radical;
  • R 7 is a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or a heteroaralkyl radical and R 8 is a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or a heteroaralkyl radical.
  • alkyl or alk refers to a saturated, straight-chain or branched hydrocarbon group which has 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, particularly preferably 1 to 6 carbon atoms, e.g. the methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, n-hexyl, 2, 2-dimethylbutyl or n-octyl group.
  • alkenyl and alkynyl refer to at least partially unsaturated, straight-chain or branched hydrocarbon groups, the 2 to 20
  • Alkenyl groups preferably have one or two (particularly preferably one) double bonds or
  • alkyl, alkenyl and alkynyl refer to groups in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or CD, such as the 2, 2, 2-trichloroethyl or the trifluoromethyl group).
  • a halogen atom preferably F or CD, such as the 2, 2, 2-trichloroethyl or the trifluoromethyl group.
  • heteroalkyl groups are groups of the formulas R ⁇ OY * -, R a _ s _ ⁇ a _ # R a -N (R b ) -Y a -, R a -CO-Y a -, R-0-CO- Y a - R a -CO-0-Y a -, R a -CO-N (R b ) -Y a -, R a -N (R b ) -CO-Y a -
  • R a -0-CO-N (R b ) -Y a -, R a -N (R b ) -CO-0-Y a -, R a -N (R b ) -CO-N (R c ) -Y a - R a -0-CO-0-Y a -, R a -N (R b ) -C ( NR d ) -N (R C ) -Y a -, R a -CS-Y a - R a -0-CS-Y a -, R a -CS-0-Y a -, R a -CS-N (R b ) -Y a -, R a -N (R b ) -CS-Y a - R a -0-CS-N (R b ) -Y a -, R a -N (R b ) -CS-Y a
  • Is -C 6 alkylene, a C 2 -C 6 alkenylene or a C 2 -C 6 alkynylene group, each heteroalkyl group containing at least one carbon atom and one or more hydrogen atoms can be replaced by fluorine or chlorine atoms.
  • heteroalkyl groups are methoxy, trifluoromethoxy, ethoxy, n-propyloxy, iso-propyloxy, tert-butyloxy, methoxymethyl, ethoxymethyl, methoxyethyl, methylamino, ethylamino, diethylamino, diethylamino, iso-propylethylamino, methylaminomethyl, ethylaminomethyl, diisopropylaminoethyl, enol ether, dimethylaminoethyl, dimethylaminoethyl, dimethylaminoethyl , Propionyl, butyryloxy, acetyloxy, methoxycarbonyl, ethoxycarbonyl, N-ethyl-N-methylcarbamoyl or N-methylcarbamoyl.
  • heteroalkyl groups are nitrile, isonitrile,
  • cycloalkyl refers to a saturated or partially unsaturated (e.g. cycloalkenyl) cyclic group which has one or more rings (preferably 1 or 2) which have a total of 3 to 14 ring carbon atoms, preferably 3 to 10 (especially 3 , 4, 5, 6 or 7) contain ring carbon atoms.
  • B. cyclic ketones such.
  • cycloalkyl groups are the cyclopropyl, cyclobutyl, cyclopentyl, spiro [4,5] decanyl, norborny, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, cubanyl, bicyclo [4.3.0] nonyl -, tetralin, cyclopentylcyclohexyl, fluorocyclohexyl or the cyclohex-2-enyl group.
  • Examples are the piperidyl, morpholinyl, urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl, oxacyclopropyl, azacyclopropyl or 2-pyrazolinyl group as well as lactams, lactones, cyclic imides and cyclic anhydrides.
  • heteroalkylcycloalkyl refers to alkylcycloalkyl groups, as defined above, in which one or more (preferably 1, 2 or 3) carbon atoms are represented by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably oxygen, sulfur or Nitrogen) are replaced.
  • Examples of such groups are alkyl heterocycloalkyl, alkyl heterocycloalkenyl, alkenyl heterocycloalkyl, alkynyl heterocycloalkyl, heteroalkylcycloalkyl, heteroalkyl heterocycloalkyl and heteroalkyl heterocylcloalkenyl, the cyclic groups being saturated or mono-, di- or trisaturated.
  • aryl or Ar refers to an aromatic group which has one or more rings which contain a total of 6 to 14 ring carbon atoms, preferably 6 to 10 (in particular 6) ring carbon atoms.
  • aryl (or Ar) also refers to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or OH, SH, NH 2 or NO 2 groups. Examples are the phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxyphenyl group.
  • heteroaryl refers to an aromatic group which has one or more rings which contain a total of 5 to 14 ring atoms, preferably 5 to 10 (in particular 5 or 6) ring atoms and one or more (preferably 1, 2, 3 or 4 ) Contain oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N).
  • heteroaryl also refers to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine or iodine atoms or OH, SH, NH 2 or NO 2 groups.
  • examples are 4-pyridyl, 2-imidazolyl, 3-phenylpyrrolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, pyridazinyl, quinolinyl, purinyl, carbazolyl , Acridinyl, pyrimidyl, 2, 3 "bifuryl, 3-pyrazolyl and isoquinolinyl groups.
  • aralkyl refers to groups which, according to the above definitions, contain both aryl and also alkyl, alkenyl, alkynyl and / or cycloalkyl groups, such as, for. B. arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylarylcycloalkyl and alkyl arylcycloalkenyl groups.
  • aralkyls are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1H-indene, tetralin, dihydronaphthalenes, indanone, phenylcyclopentyl, cumene, cyclo-hexylphenyl, fluorene and indane.
  • An aralkyl group preferably contains one or two aromatic ring systems (1 or 2 rings) with a total of 6 to 10 ring carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups with 1 or 2 to 6 carbon atoms and / or a cycloalkyl group with 5 or 6 ring carbon atoms.
  • heteroaralkyl refers to an aralkyl group as defined above in which one or more (preferably 1, 2, 3 or 4) carbon atoms are represented by an oxygen, nitrogen, silicon, selenium, phosphorus, boron or sulfur atom (preferably oxygen , Sulfur or nitrogen) are replaced, ie on groups which, according to the above definitions, are both aryl or heteroaryl and also alkyl, alkenyl, alkynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl groups contain.
  • one Heteroaralkyl group one or two aromatic ring systems (1 or 2 rings) with a total of 5 or 6 to 10 ring carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups with 1 or 2 to 6 carbon atoms and / or a cycloalkyl group with 5 or 6 ring carbon atoms, 1, 2, 3 or 4 of these carbon atoms being replaced by oxygen, sulfur or nitrogen atoms.
  • Examples are aryl heteroalkyl, aryl heterocycloalkyl, aryl heterocycloalkenyl, aryl alkyl heterocycloalkyl, aryl alkenyl heterocycloalkyl, arylalkynyl heterocyclo alkyl, aryl alkyl heterocycloalkenyl, heteroaryl alkyl, hetero aryl hetero aryl hetero aryl , Heteroarylhetero- cycloalkyl-, Heteroarylheterocycloalkenyl-, Heteroarylal- kylcycloalkyl-, Heteroarylalkylheterocycloalkenyl-, arylheteroalkylcycloalkyl- hetero-, Heteroarylheteroalkylcycloalke- nyl- and Heteroarylheteroalkylheterocycloalkyl groups, WO at the cyclic groups being saturated or mono-, di-
  • This expression also relates to groups which exclusively or additionally with unsubstituted -CC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -C-C 6 heteroalkyl, C 3 -C ⁇ 0 cycloalkyl -, C 2 -C 9 heterocycloalkyl, C 6 -C ⁇ 0 aryl, -C-C 9 heteroaryl, C 7 -C ⁇ 2 aralkyl or C 2 -Cn heteroaralkyl groups are substituted.
  • Compounds of formula (I) can contain one or more centers of chirality due to their substitution.
  • the present invention therefore encompasses all pure enantiomers and all pure diastereomers, as well as their mixtures in any mixing ratio.
  • the present invention also includes all cis / trans isomers of the compounds of the general formula (I) and mixtures thereof.
  • the present invention further encompasses all tautomeric forms of the compounds of the formula (I).
  • insoluble polymeric supports are polymers based on polystyrene (crosslinked with divinylbenzene) such as.
  • Merrifield resin bromo (4- methoxyphenyDmethyl Polystyrrol, 4- (bromomethyl) phenoxy ethyl Polystyrrol, the 2-Clorotrityl resin tentacle polymers such as Tentagel ®, silica gel, controlled pore glass (CPG), cellulose, copolymers and gold.
  • Polymeric carriers, as well as polymeric carriers modified by linkers are available from a number of companies such as Calbiochem-Novabiochem AG, Laufelfingen, Switzerland, Bachern AG, Bubendorf, Switzerland, Rapp Polymer GmbH, Tübingen, Germany, Advanced ChemTech . Louisville, KY, USA and Shearwater Corporation, Huntsville, Alabama, USA are commercially available.
  • the compounds according to the invention can be prepared by reacting compounds of the formulas (III), (IV) and (V)
  • X is a leaving group such.
  • B. F, Cl, Br, I, NR 9 b ⁇ R-, 10 OR 11 or SO n R 12 , wherein R 9 , R 10 , R 11 and R 12 are independently a hydrogen atom, an alkyl, heteroalkyl, aryl - Aralkyl, cycloalkyl, cycloaralkyl, heterocycloalkyl, heteroaralkyl, or a heteroaryl radical and n 0, 1, 2 or 3.
  • reaction conditions e.g. addition of ammonia in methanol
  • compounds of the formula (Ha) can be prepared directly:
  • R 4 is particularly preferably a group of the formula COOMe, COOEt or COO' ⁇ u.
  • R 5 is a hydrogen atom.
  • R 6 is furthermore preferably a hydrogen atom.
  • R 7 is a C ⁇ -C 6 alkyl, C 2 -C 6 - alkenyl, C 2 -C 6 alkynyl, C ⁇ -C5 heteroalkyl, C 6 - or C ⁇ 0 - aryl , C 5 -C 9 heteroaryl-, C 3 -C ⁇ 0 cycloalkyl-, C 4 -C n - alkylcycloalkyl-, C 3 -C ⁇ 0 heteroalkylcycloalkyl-, C 2 -C 9 - heterocycloalkyl-, C 7 -C 12 aralkyl or a C 5 -C 2 heteroaralkylres,
  • aprotic solvent such as. B. tetrahydrofuran (THF), dioxane, diethyl ether, acetonitrile or methylene chloride, with ethers such as. B. THF are particularly preferred.
  • the compounds (III), (IV) and (V) are preferably used in equimolar amounts.
  • reaction temperatures are in the range from -100 ° C. to 100 ° C., reaction temperatures from -80 ° C. to 60 ° C. being particularly preferred (temperatures from -25 ° C. to 25 ° C. are particularly preferred).
  • the reaction is optionally carried out in a microwave reactor.
  • a Lewis acid such as. B. boron trifluoride etherate, trimethyl aluminum, lithium chloride, aluminum trichloride, zinc chloride (ZnCl 3 ), ytterbium triflate, magnesium triflate, magnesium bromide, zirconium chloride (ZrCl 4 ), titanium (IV) chloride, zinc triflate (Zn (OTf) 2 ), scandium triflate (Sc (triflate) ) 3 ), hafnium triflate (Hf (OTf) 4 ) or tin tetrachloride may be preferred.
  • a Lewis acid such as. B. boron trifluoride etherate, trimethyl aluminum, lithium chloride, aluminum trichloride, zinc chloride (ZnCl 3 ), ytterbium triflate, magnesium triflate, magnesium bromide, zirconium chloride (ZrCl 4 ), titanium (IV) chloride, zinc triflate (Zn (OTf) 2 ),
  • compound (III) is first dissolved in the solvent with the Lewis acid and then (preferably after 5 to 30 minutes) compounds (IV) and (V) are added.
  • a key compound in the synthesis of some of the tubulysin derivatives described above is an amino acid derivative of the general formula (VI):
  • This compound can be synthesized in a simple manner using the process described here by reacting compounds of the formulas (IV), (VII) and (VIII)
  • PG is an amino protecting group and R 14 is a hydrogen atom, an alkyl or a heteroalkyl radical. This method is also encompassed by the present invention.
  • PG is preferably a Boc group
  • R is a hydrogen atom
  • R 13 is a methyl, an ethyl or a tert-butyl group.
  • an isoleucine derivative of the formula (IX) is used as the thiocarboxylic acid (general formula IV),
  • tubulysins of the formula (I) can be carried out using the following steps starting from compound (XI): Coupling with N-pipecolic acid to compound (XII)
  • the reaction is hydrolyzed with 6 ml of water and mixed with 6 ml of ethyl acetate.
  • the aqueous phase is separated off and the organic phase is washed 3 times with 3 ml of saturated sodium hydrogen carbonate solution, 3 times with 3 ml of 5% citric acid and 2 times with 3 ml of saturated sodium chloride solution.
  • the ethyl acetate phase is dried over sodium sulfate and evaporated.
  • the raw product is purified by means of chromatotrography.
  • Example 15 The compound from Example 15 (0.1 mmol) is dissolved in 2 ml dichloromethane (DCM) and 0.1 ml trifluoroacetic acid (TFA) and stirred for 1 h at room temperature. The DCM / TFA mixture is then removed in vacuo and the residue is purified by HPLC.
  • DCM dichloromethane
  • TFA trifluoroacetic acid
  • Example 16 The compound from Example 16 (0.1 mmol) is dissolved in 2 ml of dichloromethane (DCM) and 0.1 ml of trifluoroacetic acid (TFA) and stirred at room temperature for 1 h. Subsequently the DCM / TFA mixture is removed in vacuo and the residue is purified by HPLC.
  • DCM dichloromethane
  • TFA trifluoroacetic acid
  • Example 17 The compound from Example 17 (0.1 mmol) is dissolved in 2 ml of dichloromethane (DCM) and 0.1 ml of trifluoroacetic acid (TFA) and stirred at room temperature for 1 h. The DCM / TFA mixture is then removed in vacuo and the residue is purified by HPLC.
  • DCM dichloromethane
  • TFA trifluoroacetic acid

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  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un nouveau procédé de production d'esters thiazol-2-ylméthyliques substitués correspondant à la formule générale (II) par réaction multicomposant de composés correspondant aux formules (III), (IV) et (V). Ces composés offrent avant tout un grand intérêt dans la synthèse de tubulysines et de dérivés de tubulysine.
PCT/EP2003/007414 2002-07-09 2003-07-09 Procede de production d'esters thiazol-2-ylmethyliques substitues WO2004005269A1 (fr)

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AU2003250014A AU2003250014A1 (en) 2002-07-09 2003-07-09 Method for producing substituted thiazol-2-yl methyl esters

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DE2002130872 DE10230872A1 (de) 2002-07-09 2002-07-09 Verfahren zur Herstellung von substituierten Thiazol-2-ylmethylestern
DE10230872.1 2002-07-09

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Cited By (17)

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Publication number Priority date Publication date Assignee Title
EP2409983A1 (fr) 2010-07-19 2012-01-25 Leibniz-Institut für Pflanzenbiochemie (IPB) Analogues de la tubulysine
WO2012171020A1 (fr) 2011-06-10 2012-12-13 Mersana Therapeutics, Inc. Conjugués de médicament-protéine-polymère
CN103333133A (zh) * 2013-06-13 2013-10-02 西北师范大学 一种Tubulysin家族化合物关键中间体TUV的合成方法
WO2014093640A1 (fr) 2012-12-12 2014-06-19 Mersana Therapeutics,Inc. Conjugués hydroxy-polymère-médicament-protéine
WO2014093394A1 (fr) 2012-12-10 2014-06-19 Mersana Therapeutics, Inc. Conjugués protéine-polymère-médicament
WO2015127685A1 (fr) 2014-02-28 2015-09-03 Hangzhou Dac Biotech Co., Ltd Lieurs chargés et leurs utilisations pour la conjugaison
WO2015151081A2 (fr) 2015-07-12 2015-10-08 Suzhou M-Conj Biotech Co., Ltd Lieurs de pontage pour la conjugaison d'une molécule de liaison cellulaire
EP3210627A1 (fr) 2012-07-12 2017-08-30 Hangzhou Dac Biotech Co., Ltd Conjugués de molécules de liaison cellulaire à des agents cytotoxiques
US10131682B2 (en) 2012-11-24 2018-11-20 Hangzhou Dac Biotech Co., Ltd. Hydrophilic linkers and their uses for conjugation of drugs to a cell binding molecules
WO2019051322A1 (fr) * 2017-09-08 2019-03-14 Seattle Genetics, Inc. Procédé de préparation de tubulysines et d'intermédiaires de celles-ci
US10232051B2 (en) 2015-07-15 2019-03-19 Hangzhou Dac Biotech Co., Ltd. Acetylenedicarboxyl linkers and their uses in specific conjugation of a cell-binding molecule
CN109912683A (zh) * 2017-12-13 2019-06-21 杭州多禧生物科技有限公司 一种细胞毒素分子、偶联物及其制备方法和应用
WO2021000067A1 (fr) 2019-06-29 2021-01-07 杭州多禧生物科技有限公司 Conjugué molécule de liaison cellulaire-dérivé de tubulysine et méthode de préparation associée
EP3888691A1 (fr) 2016-11-14 2021-10-06 Hangzhou Dac Biotech Co., Ltd. Lieurs de conjugaison, conjugués médicament-molécule de liaison à une cellule contenant lesdits lieurs, procédés de préparation et d'utilisation de tels conjugués avec les lieurs
US11229708B2 (en) 2015-12-04 2022-01-25 Seagen Inc. Conjugates of quaternized tubulysin compounds
WO2023078273A1 (fr) 2021-11-03 2023-05-11 Hangzhou Dac Biotech Co., Ltd. Conjugaison spécifique pour un conjugué anticorps-médicament
US11793880B2 (en) 2015-12-04 2023-10-24 Seagen Inc. Conjugates of quaternized tubulysin compounds

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Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9371358B2 (en) 2010-07-19 2016-06-21 Leibniz-Institut fur Pflanzenbiochemie Tubulysin analogues
WO2012010287A1 (fr) 2010-07-19 2012-01-26 Leibniz-Institut Für Pflanzenbiochemie Analogues de tubulysine
EP2409983A1 (fr) 2010-07-19 2012-01-25 Leibniz-Institut für Pflanzenbiochemie (IPB) Analogues de la tubulysine
WO2012171020A1 (fr) 2011-06-10 2012-12-13 Mersana Therapeutics, Inc. Conjugués de médicament-protéine-polymère
EP3228325A1 (fr) 2011-06-10 2017-10-11 Mersana Therapeutics, Inc. Conjugués protéine-polymère-médicament
EP3348280A1 (fr) 2012-07-12 2018-07-18 Hangzhou Dac Biotech Co., Ltd Conjugués de molécules de liaison cellulaire à des agents cytotoxiques
EP3210627A1 (fr) 2012-07-12 2017-08-30 Hangzhou Dac Biotech Co., Ltd Conjugués de molécules de liaison cellulaire à des agents cytotoxiques
US10131682B2 (en) 2012-11-24 2018-11-20 Hangzhou Dac Biotech Co., Ltd. Hydrophilic linkers and their uses for conjugation of drugs to a cell binding molecules
WO2014093394A1 (fr) 2012-12-10 2014-06-19 Mersana Therapeutics, Inc. Conjugués protéine-polymère-médicament
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