EP2699268A2 - Neue binder-wirkstoff konjugate (adcs) und ihre verwendung - Google Patents

Neue binder-wirkstoff konjugate (adcs) und ihre verwendung

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Publication number
EP2699268A2
EP2699268A2 EP12718624.5A EP12718624A EP2699268A2 EP 2699268 A2 EP2699268 A2 EP 2699268A2 EP 12718624 A EP12718624 A EP 12718624A EP 2699268 A2 EP2699268 A2 EP 2699268A2
Authority
EP
European Patent Office
Prior art keywords
group
hydrogen
formula
denotes
point
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.)
Withdrawn
Application number
EP12718624.5A
Other languages
German (de)
English (en)
French (fr)
Inventor
Hans-Georg Lerchen
Lars Linden
Sherif El Sheikh
Jörg WILLUDA
Charlotte Christine KOPITZ
Joachim Schuhmacher
Simone Greven
Christoph Mahlert
Beatrix Stelte-Ludwig
Sven Golfier
Rudolf Beier
Iring Heisler
Axel Harrenga
Karl-Heinz Thierauch
Sandra Bruder
Heike Petrul
Hannah JÖRIßEN
Sandra Borkowski
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.)
Seagen Inc
Original Assignee
Seattle Genetics Inc
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 Seattle Genetics Inc filed Critical Seattle Genetics Inc
Priority to EP19150066.9A priority Critical patent/EP3501546A3/de
Priority to EP12718624.5A priority patent/EP2699268A2/de
Publication of EP2699268A2 publication Critical patent/EP2699268A2/de
Withdrawn legal-status Critical Current

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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0207—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)4-C(=0), e.g. 'isosters', replacing two amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon 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
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06052—Val-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present application relates to novel, directed against the target C4.4a binder-drug conjugates (ADCs) of ⁇ , ⁇ -dialkylauristatins, active metabolites of these ADCs, methods for producing these ADCs, the use of these ADCs for the treatment and / or prevention of Diseases and the use of these ADCs for the preparation of medicaments for the treatment and / or prevention of diseases, especially hyperproliferative and 7 or angiogenic diseases such as cancer.
  • Such treatments may be monotherapy or in combination with other medicines or other therapeutic measures.
  • Cancers are the result of uncontrolled cell growth in a variety of tissues, in many cases the new cells invade existing tissues (invasive growth) or they metastasize to distant organs. Cancers occur in various organs and often have tissue-specific disease courses. Therefore, the term cancer as a generic term describes a large group of defined diseases of various organs, tissues and cell types.
  • chemotherapeutic agents administered parenterally today are often not targeted to tumor tissue or tumor cells, but are nonspecifically distributed in the body by systemic administration, i. even in places where drug exposure is undesirable, such as in healthy cells, tissues, and organs. This can lead to unwanted side effects and even serious general toxic effects, which then often severely limit the therapeutically usable dose range of the active substance or require a complete cessation of the medication.
  • trastuzumab Herceptin
  • rituximah Renillab
  • cetuximab Erbitux
  • bevacizumab Avastin
  • small molecule drug binders can also be used as binders that selectively bind to a particular target, such as a receptor [see, e.g. E. Ruoslahti et al., Science 279, 377-380 (1998); D. Karkan et al., PLoS ONE 3 (6), e2469 (June 25, 2008)]. Also known are conjugates of cylotoxic agent and addressing ligand, which have a defined cleavage site between ligand and drug to release the drug.
  • target breakpoint may be, for example, in a peptide chain which can be selectively cleaved at a particular site by a specific enzyme at the site of action [see, e.g. R. A, Firestone and L.A. Telan, US Patent Application US 2002/0147138].
  • C4.4a (gene: LYPD3) was first described as a metastasis-associated cell surface protein in rat pancreatic tumor cells (R Harborl M. et al., Oncogene 1998, 17 (15): 1989-2002). Human C4.4a was isolated from its placental cDNA library (Würfel, J. et al., Gene 2001, 262: 35-41). C4.4a shows structural homology to the uPA receptor and contains two LY6 domains that share the typical three-finger folding motif and are linked by 9 disulfide bonds (Jacobsen B.
  • C4.4a is anchored in the cell via glycophosphatidylinositol (GPI).
  • GPI glycophosphatidylinositol
  • the protein is highly glycosylated and contains numerous - and O- glycosylation sites.
  • C4.4a shows strong expression in tumor cells of lung cancer, colon cancer, breast cancer, uterine cancer pancreatic cancer, kidney cancer, head and neck tumors and melanoma.
  • RNA analyzes showed C4.4a expression in - 50% of primary lung tumors and -75% of lung cancer metastases, whereas expression in healthy lung tissue was undetectable (Würfel J. et al., Gene 2001, 262: 35- 41).
  • C4.4a can be used as a prognostic marker, with high C4.4a expression correlating with poor prognosis (Hansen L. et al ,, Lung Cancer 2007, 58: 260-266).
  • colon cancer C4.4a is cleaved off the tumor cell surface and can be used as a prognostic serum marker (Konishi, K., et al., Cancer Science 2010).
  • a detailed expression analysis of melanoma revealed that C4.4a is present in ⁇ 60% of the primary malignancies Melanoma and is expressed in 100% of lymph node and skin metastases (sammlungr S. et al., Juvest Dermatol., 2001, 116 (2): 344-347).
  • C4.4a is an ideal target for tumor therapy because C4.4a expression in healthy tissues is restricted to skin keratinocytes and esophageal endothelial cells as well as placental cells (Würfel J. et al., Gene 2001, 262: 35-41).
  • WO01 / 23553 describes the use of a C4.4a inhibitor (eg an anti-C4.4a antibody) which can inhibit C4.4a expression or activity in cancer therapy. The exact function of C4.4a is unknown.
  • C4.4a is thought to play a role in tumor cell invasion, presumably through interaction with the extracellular matrix (Renderl M, et al., Oncogene 1998, 17 (15): 1989-2002; Paret C. et al. British Journal of Cancer 2007, 97: 1146-1156).
  • Potential ligands are laminin I and 5, as well as galectin 3 (Paret C, Int J. Cancer 2005, 115: 724-733).
  • Auristatin E (AE) and monomethylauristatin E (MMAE) are synthetic analogues of the statins, a special group of linear pseudopeptides originally isolated from marine sources, some of which have very potent cytotoxic activity against tumor cells [for a review, see, eg GR Pettit, Prague. Chem. Org. Prod. 70, 1-79 (1997); GR Pettit et al, Anti-Cancer Dr g Design 10, 529-544 (1995); GR Pettit et al, AntiCancer Drug Design 13, 243-277 (1998) 1.
  • MMAE Monomethylauristatin E
  • MMAE has the disadvantage of a comparatively high systemic toxicity.
  • MMAE is used in particular in conjunction with enzymatically cleavable valine citrulline linkers in the ADC setting for more targeted tumor therapy [WO 2005/081711-A2; S.O. Doronina et al., Bioconjugate Chem. 17, 114-124 (2006)].
  • MMAE is preferably released intracellularly from corresponding ADCs.
  • MMAE is in an application in the form of (ADCs) not compatible with linker (linker) between antibody and drug, which have no enzymatically cleavable target breakpoint [SO Doronina et al., Bioconjugate Chem. 17, 114-124 (2006)].
  • Monomethylauristatin F is an auristatin derivative having a C-terminal phenylalanine moiety which has only moderate anti-proliferative activity compared to MMAE. This is most likely due to the free carboxyl group which, due to its polarity and charge, adversely affects the cellularity of this compound.
  • MMAF-OMe methyl ester of MMAF
  • MMAF-OMe methyl ester of MMAF
  • MMAF-OMe has been described as a neutrally charged, prodrug prodrug, which has several orders of magnitude increased in vitro cytotoxicity to various carcinoma cell lines compared to MMAF [SO Doronina et al., Bioconjugate Chem. 17, 114-124 (2006)]. It is believed that this effect is caused by MMAF itself, which is rapidly released by intracellular ester hydrolysis after uptake of the prodrug into the cells.
  • active compound compounds based on simple ester derivatives are generally subject to the risk of chemical instability as a result of unspecific ester hydrolysis independent of the intended site of action, for example by esterases present in the blood plasma; this can significantly limit the applicability of such compounds in therapy.
  • MMAF Monomethylauristatin F
  • auristatin analogues with a C-terminal, amidically substituted phenylalanine unit are described in WO 01/18032-A2.
  • WO 02/088172-A2 and WO 2007/008603-A1 claim MMAF analogs which relate to side-chain modifications of phenylalanine, and in WO 2007/008848-A2 those in which the carboxyl group of phenylalanine is modified , Auristatin conjugates linked via the C-terminus have recently been described in WO 2009/1 17531 -AI [see also S.O. Doronina et al., Bioconjugate Chem. 19, 1960-1963 (2008) 1.
  • auristatin derivatives such as MMAE and MMAF are also substrates for transporter proteins which are expressed by many tumor cells, which can lead to a development of resistance to these active substances.
  • ADCs novel binder-drug conjugates
  • the present invention relates to binder-active compound conjugates of the general formula (Ia)
  • n is a number from 1 to 50
  • AK is a binder
  • group ⁇ -G-L'-BL 2 - ⁇ is a linker
  • ⁇ denotes the linking parts with the group AK and ⁇ denotes the point of attachment with the nitrogen atom, D for a group of the formula
  • n ' denotes the point of attachment to the nitrogen atom
  • R 1 is hydrogen or methyl
  • R 2 is isopropyl, isobutyl, sec-butyl, fer. '- butyl, phenyl, benzyl, 1 -
  • # 5 denotes the site of attachment to the carbonyi group, with the NO group contained therein being a mono- or bicyclic, optionally substituted heterocycle of the formula
  • R ' is hydrogen, methyl, ethyl, propyl, tert. Butyl, benzyl or adamantylmethyl,
  • R 8 is hydrogen or methyl
  • R 9 is hydrogen, methyl, ethyl, propyl or benzyl, or
  • R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle
  • R i 0 is benzoyl
  • R 11 is benzyl which may be substituted in the phenyl group by methoxycarbonyl or carboxyl,
  • R 5 is hydrogen, methyl or a group of the formula
  • R 12 is phenyi which is reacted with methoxycarbonyl, carboxyi or a group of the formula S (C) ⁇ ⁇ ()! ⁇ can be substituted,
  • R ' 3 is phenyi which may be substituted with methoxycarbonyl or carboxyi
  • R zo is hydrogen or hydroxy
  • T 2 represents phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl
  • R J5 is methyl or hydroxy, and their salts, solvates and solvates of the salts.
  • Compounds of the invention are the compounds of the formula (ia) and (I) and their salts, solvates and solvates of the salts, the compounds of the formulas (Ia) and (I) of the following formulas and their salts, solvates and solvates of the salts and the compounds of formula (Ia) and (I), referred to below as exemplary embodiments, and their salts, solvates and solvates of the salts, as far as the compounds of formula (Ia) and (I) below are not already salts , Solvates and solvates of the salts.
  • the compounds according to the invention may exist in different stereoisomeric forms, ie in the form of configurational isomers or optionally also as conformational isomers (enantiomers and / or diastereomers, including those of atropisomers).
  • the present invention therefore includes the enantiomers and diastereoisomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform constituents can be in a known manner isolate; Preferably, chromatographic methods are used for this, in particular HPLC chromatography on achiral or chiral phase.
  • the present invention encompasses all tautomeric forms.
  • the present invention also includes all suitable isofopic variants of the compounds of the invention.
  • An isotopic variant of a compound according to the invention is understood here as meaning a compound in which at least one atom within the compound according to the invention is exchanged for another atom of the same atomic number but with a different atomic mass than the atomic mass that usually or predominantly occurs in nature.
  • isotopes which can be incorporated into a compound of the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 6 Cl , 82 Br, i23 i, 124 f, 129 1 and I3L L
  • Certain isotopic variations of a compound of the invention, in particular those in which one or more radioactive isotopes are incorporated, may be useful, for example, for studying the mechanism of action or of drug distribution in the body; Due to the comparatively easy production and detectability, compounds labeled with 3 H or 14 C isotopes are particularly suitable for this purpose.
  • isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability of the compound, such as prolonging the body's half-life or reducing the required effective dose;
  • isotopic variants of the compounds according to the invention can be prepared by the processes known to the person skilled in the art, for example by the methods described below and the rules given in the exemplary embodiments, by corresponding Isotopic modifications of the respective reagents and / or starting compounds can be used.
  • Salts used in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.
  • Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid. acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of example, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms.
  • alkali metal salts for example sodium and potassium salts
  • alkaline earth metal salts for example calcium and magnesium salts
  • ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms such as, by way of example and by way of example, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms.
  • Atoms such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylpiperidine, N-methylmorpholine, arginine, lysine and 1,2-ethylenediamine.
  • Solvates in the context of the invention are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.
  • the present invention also includes prodrugs of the compounds of the invention.
  • prodrugs refers to compounds which themselves may be biologically active or inactive, but are converted during their residence time in the body to compounds of the invention (for example metabolically or hydrolytically).
  • (C 1 -C 4) -alkyl in the context of the invention represent a linear or branched alkyl radical having 1 to 4 carbon atoms, by way of example and preferably: methyl, ethyl, ⁇ -propyl, isopropyl, ⁇ -butyl, isobutyl, ⁇ -methylpropyl and teri .-Bufyl.
  • Alkanediyl is in the context of the invention a linear, ⁇ , ⁇ -divalent alkyl radical having the particular number of carbon atoms.
  • Examples which may be mentioned by way of example and with preference are: methylene, ethane-1,2-diyl (1,2-ethylene), propane-1,3-diyl (1,3-propylene), butane-1,4-diyl (1,4) Butylene), pentane-l, 5-diyl (1,5-pentylene), hexane-1,6-diyl (1,6-hexylene), heptane-l, 7-diyl (1,7-hexylene), octane l, 8-diyl (1,8-octylene), nonane-l, 9-diyl (1,9-nonylene), decane-l, 10-diyl (1, 10-decylene).
  • CyCTl-cycloalkyl or 3- to 7-membered carbocycle in the context of the invention stands for a monocyclic, saturated cycloalkyl group having 3 to 7 carbon atoms and may be mentioned by way of example and preferably: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • the side group of a q-amino acid in the meaning of R 19 comprises both the side groups of the naturally occurring ⁇ -amino acids and the side groups of homologues and isomers of these ⁇ -amino acids.
  • the ⁇ -amino acid can be present in both the L and the D configuration or else as a mixture of the L and D form.
  • side groups which may be mentioned are: methyl (alanine), propan-2-yl (valine), propan-1-yl (norvaline), 2-methylpropan-1-yl (leucine), 1-methylpropane-1-ylyl ( Isoleucine), butan-1-yl (norleucine), ferric butyl (2-heptabutylglycine), phenyl (2-phenylglycine), benzyl (phenylalanine), p-hydroxybenzyl (tyrosine), indole-3 ylmetyl (tryptophan), imidazol-4-ylmethyl (histidine), hydroxymethyl (serine), 2-hydroxyethyl (homoserine), 1-hydroxyethyl (threonine), mercaptomethyl (cysteine), methylthiomethyl (S-methylcysteine), 2- Mercaptoeihyl (homocysteine), 2-methylthioethyl (methionine),
  • Preferred ⁇ -amino acid side-groups in the meaning of R 1 " are methyl (alanine), propan-2-yl (valine), 2-methylpropan-1-yl (leucine), benzyl (phenylalanine), imidazole-4 -ylmethyl (histidine), hydroxymethyl (serine), 1-hydroxyethyl (threonine), 4-aminobutan-1-yl (lysine), 3-aminopropan-1-yl (ornithine), 2-aminoethyl (2,4-diaminobutyric acid) , Aminomethyl (2,3-diaminopropionic acid), 3-guanidinopropan-1-yl (arginine), in each case the L-configuration is preferred.
  • a 4- to 7-membered heterocycle represents in the context of the invention a monocyclic, saturated heterocycle having a total of 4 to 7 ring atoms, which contains one or two ring heteroatoms from the series, O, S, SO and / or SO 2 and is linked via a ring carbon atom or optionally a ring nitrogen atom - to 7-membered heterocycle having one or two ring heteroatoms from the series N, O and / or S, particularly preferably a 5-membered or 6-membered heterocycle having one or two Ri
  • examples include: azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, thiolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, polypholinyl, thiomorpholinyl, hexahydroazepinyl and
  • radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. Substitution with one or two identical or different substituents is preferred. Particularly preferred is the substitution with a substituent.
  • linker is broadly understood to mean a chemical entity comprising a covalent bond or an array of atoms that covalently attaches a binder to an agent, Preferably, the term “linker” is used as an array of atoms in the sense of Understand the present invention, which covalently attaches a binder to a drug.
  • linkers may be, for example, divalent chemical moieties such as alkyldiyls, aryldiyls, heteroaryldyls, heterocyclyldyls, dicarbonylic acid esters, dicarbonylic acid amides.
  • binder is broadly understood to mean a molecule that binds to a target molecule present on a particular target cell population to be targeted with the binder-drug conjugate includes, for example, lectins, proteins capable of binding certain sugar chains, or phospholipid-binding proteins, such as, for example, high molecular weight proteins (binding proteins), polypeptides or peptides (binding peptides), non-peptidic (eg, aptamers (US5,270,163) (review articles) Rev.
  • lectins proteins capable of binding certain sugar chains
  • phospholipid-binding proteins such as, for example, high molecular weight proteins (binding proteins), polypeptides or peptides (binding peptides), non-peptidic (eg, aptamers (US5,270,163) (review articles) Rev.
  • Binding proteins are eg antibodies and antibody fragments or such as Affibodies, Adnectins, Anticalins, DARPins, Avimers, Nanobodies (reviewed by Gebauer M. et al., Curr. Opinion in Chem. Biol. 2009; 13: 245-255; Nuttall SD et al., Curr. Opinion in Pharmacology 2008; 8: 608-617).
  • Binding peptides are, for example, ligands of a ligand-receptor pair, such as VEGF of the ligand-receptor pair VEGF / KDR, such as transferrin of the ligand receptor pair Transferrin Traiisferriii receptor or cytokine / cytokine receptor, such as TNF alpha of the ligand receptor pair TNFalpha 'TNFalpha receptor.
  • ligands of a ligand-receptor pair such as VEGF of the ligand-receptor pair VEGF / KDR
  • transferrin of the ligand receptor pair Transferrin Traiisferriii receptor or cytokine / cytokine receptor, such as TNF alpha of the ligand receptor pair TNFalpha 'TNFalpha receptor.
  • Preferred binders according to the invention are (in particular human, monoclonal) antibodies or antigen-binding antibody fragments which bind to C4.4a, in the case of anti-C4.4a antibodies n, ie the number of toxophore molecules per antibody molecule, is preferably in the range from 1 to 10, more preferably 2 to 8.
  • a “target molecule” is broadly understood to be a molecule present in the target cell population, and may be a protein (eg, a growth factor receptor) or a non-peptidic molecule (eg, a sugar or phospholipid)
  • the term "extracellular" target molecule describes a cell-bound target molecule located on the outside of a cell, or the part of a target molecule that is on the outside of a cell, ie, a binder can bind to an intact one Bind cell to its extracellular target molecule.
  • An extracellular targeting molecule may be anchored in the cell membrane or be part of the cell membrane.
  • the person skilled in the art knows methods to identify extracellular target molecules. For proteins, this can be done by determining the transmembrane domain (s) and the orientation of the protein in the membrane. This information is usually stored in protein databases (eg SwissProt).
  • cancer target molecule describes a target molecule that is more abundant on one or more types of cancer cells as compared to non-cancerous cells of the same tissue type, Preferably, the cancer target molecule is on one or more cancer cell types compared to non-cancerous cells of the same Tissue type selectively present, selectively delineating at least two-fold accumulation on cancer cells compared to non-cancer cells of the same tissue type (a "selective cancer target molecule”).
  • selective cancer target molecule allows the selective therapy of cancer cells with the conjugates of the invention.
  • the binder can be linked via a linkage with the linker.
  • linkage of the binder can be effected by means of a heteroatom of the binder.
  • Heterocycles of the invention that can be used for linking are sulfur (in one embodiment via a sulthydryl group of the binder), oxygen (according to the invention by means of a carboxyl or hydroxyl group of the binder) and nitrogen (in one embodiment via a primary or secondary amine group or atnide group of the Binders).
  • Preferred according to the invention is the conjugation of the toxophore to the antibody via one or more sulfur atoms of cysteine residues of the antibody and or via one or more NH groups of lysine residues of the antibody.
  • These heating atoms may be present in the natural binder or introduced by chemical or molecular biological metliodes.
  • the linkage of the binder with the toxophore has only a small influence on the binding activity of the binder to the target molecule. In a preferred embodiment, the linkage has no influence on the binding activity of the binder to the target molecule.
  • an immunoglobulin molecule preferably comprises a molecule having four polypeptide chains, two heavy chains (H chains) and two light chains (L chains), which are typically linked by disulfide bridges.
  • Each heavy chain comprises a heavy chain variable domain (abbreviated VH) and heavy chain constant domain.
  • the heavy chain constant domain may include three domains CHI, CH2 and CH3.
  • Each light chain comprises a variable domain (abbreviated VL) and a constant domain.
  • the constant domain of the light chain comprises a domain (abbreviated to CL).
  • the VH and VL domains can be further subdivided into regions of hypervariability, also called complementarity determining regions (abbreviated to CDR) and regions of lower sequence variability (FR).
  • CDR complementarity determining regions
  • FR regions of lower sequence variability
  • Each VH and VL region typically consists of three CDRs and up to four FRs.
  • FRi complementarity determining regions
  • An antibody can be obtained from any suitable species, eg, rabbit, llama, camel, mouse, or rat. In an execution form! the antibody is of human or murine origin.
  • An antibody may be, for example, human, humanized or brain.
  • the term “monoclonal” antibody refers to antibodies obtained from a population of substantially homogeneous antibodies, ie, individual antibodies of the population are identical except for naturally occurring mutations which can occur in small numbers.Monoclonal antibodies recognize with high specificity a single antigenic binding site The term “monoclonal antibody” does not refer to any particular method of production.
  • the term “intact” antibody refers to antibodies comprising both an antigen-binding domain and the light and heavy chain constant domain.
  • the constant domain may be a naturally occurring domain, or a variant thereof in which one or more amino acid positions have been altered.
  • modified intact antibody refers to intact antibodies fused to another non-antibody polypeptide or protein via their amino terminus or carboxy-terminus via a covalent bond (eg, a peptide linkage) modified to introduce reactive cysteines at defined sites to facilitate coupling to a toxophore (see Junutula et al., Nat Biofechnol., 2008 Aug; 26 (8) i925-32).
  • human antibody refers to antibodies that can be obtained from a human or that are synthetic human antibodies
  • a "synthetic" human antibody is an antibody that is available in part or in whole from synthetic sequences in silico that have been analyzed based on human antibody sequences.
  • a human antibody may be encoded by a nucleic acid isolated from a library of antibody sequences of human origin. An example of such antibodies is in Söderlind et al., Ature Biotech. 2000, 18: 853-856.
  • humanized or “chimeric” antibody describes antibodies consisting of a non-human and a human sequence portion. In these antibodies, part of the sequences of the human immunoglobulin (recipient) is replaced by sequence portions of a non-human immunoglobulin (donor).
  • the donor is a murine immunoglobulin in many cases.
  • amino acids of the CDR of the recipient are replaced with amino acids of the donor. Sometimes amino acids of the framework are replaced by corresponding amino acids of the donor.
  • the humanized antibody contains amino acids that were not contained in either the recipient or the donor and that would be inserted during optimization of the antibody.
  • the variable domains of the donor immunoglobulin, or even the entire Fab fraction, ie VL-CL and VII + CHI are fused to the constant regions of a human antibody.
  • complementarity determining region refers to those amino acids of a variable antibody domain necessary for binding to the antigen.
  • Each variable region typically has three CDR regions, referred to as CDR1, CDR2 and CDR3.
  • Each CDR region may comprise amino acids as defined by Kabat and / or amino acids of a hypervariable loop defined by Chotia.
  • the Kabat definition includes, for example, the region of approximately amino acid position 24-34 (CDR1), 50-56 (CDR2) and 89-97 (CDR3) of the variable light chain and 31-35 (CDR1), 50-65 (CDR2).
  • CDR3 variable heavy chain Kabat et al., Sequences of Proteins of Immulological Filter, 5th ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)).
  • the definition according to Chotia includes the region of approximately amino acid position 26-32 (CDR1), 50-52 (CDR2) and 91-96 (CDR3) of the variable light chain and 26 32 (CDR1), 53-55 (CDR2) and 96 101 (CDR3) of the variable heavy chain Chothia and Lesk; J Mol Biol 196: 901-917 (1987)).
  • a CDR may comprise amino acids from a CDR region as defined by Kabat and Chotia.
  • antibodies can be grouped into different classes. There are five major classes of intact antibodies: IgA, IgD, IgE, IgG and IgM, several of which can be broken down into other subclasses. (Isotypes), eg IgGl, IgG2, IgG3, TgG4, TgAl and IgA2.
  • the heavy chain constant domain corresponding to the different classes are referred to as [alpha / a], [delta / ⁇ ], [epsilon / ⁇ ], [garnma / ⁇ ] and [my / ⁇ ]. Both the three-dimensional structure and the subunit structure of antibodies are known.
  • the term "functional fragment” or "antigen-binding antibody fragment” of an antibody / immunoglobulin is defined as a fragment of an antibody / immunoglobulin (eg, the variable domains of an IgG) which still comprises the antigen binding domains of the antibody / immunoglobulin
  • Antigen binding domain typically comprises one or more hypervariable regions of an antibody, eg the CDR1, CDR2 and / or CDR3 region.
  • the "framework” or “framework” region of an antibody may also play a role in binding the antibody to the antigen.
  • the framework region provides the framework for the CDRs.
  • the antigen-binding domain comprises at least amino acids 4 to 103 of the variable light chain and amino acids 5 to 109 of the variable heavy chain, more preferably amino acids 3 to 107 of the variable light chain and 4 to 111 of the variable heavy chain, most preferably the complete ones variable light and heavy chains, ie amino acid 1 109 of the VL and 1 to 113 of the VH (numbering according to WO97 / 08320).
  • “Functional fragments” or “antigen-binding antibody fragments” of the invention do not exhaustively include Fab, Fab ', F (ab') 2 and Fv fragments, diabodies, single domain antibodies (DAbs), linearae antibodies, single chain antibodies (single-chain Fv , abbreviated scFv); and multispecific, such as bi- and tri-specific, antibodies formed from antibody fragments CA K Borrebaeck, editor (1995) Antibody Engineering (Breakthroughs in Molecular Biology), Oxford University Press; R. Kontermann & S. Duebel, editors (2001) Antibody Engineering (Springer Laboratory Manual), Springer Verlag). Antibodies other than "multi-specific” or “multi-functional” are those with identical binding sites.
  • Multispecific antibodies may be specific for different epitopes of an antigen or specific for epitopes of more than one antigen (see eg WO93 / 17715, WO92 / 08602, WO91 / 00360, WO92 / 05793, Tuti, et al., 1991, J. Immunol., 147: 60 69; U.S. Patent Nos. 4,474,893; 4,7 14,68 1; 4,925,648; 5,573,920; 5,601,819; or Kostelny et al., 1992, J. Immunol. 148: 1547 1553). , An F (from ').
  • Fab molecule can be engineered to reduce or completely prevent the number of intermolecular disulfide interactions that occur between the Chi and CL domains.
  • “Functional fragments” or “antigen-binding antibody fragments” may be fused to another non-antibody polypeptide or protein via their amino-terminus or carboxy-terminus via a covalent bond (eg, a peptide linkage).
  • you can and antigen-binding fragments are modified to introduce reactive cysteines at defined sites to facilitate coupling to a toxophore (see Junutula et al., Nat Biotechnol., 2008 Aug; 26 (8): 925-32),
  • Polyclonal antibodies can be prepared by methods known to those of ordinary skill in the art.
  • Monoclonal antibodies can be prepared by methods known to those of ordinary skill in the art (Köhler and Milstein, Nature, 256, 495-497, 1975).
  • Humanized human monoclonal antibodies can be prepared by methods known to those of ordinary skill in the art (Olsson et al., Meth Enzymol., 92, 3-16 and Cabilly et al., US 4,816,567 or Boss et al US 4,816,397).
  • Candidates of the invention may be recombinant
  • Antibodies made up of a large number of healthy volunteers can also be made by known recombinant DNA technology. The
  • Nucleic acid sequence of an Andlauer can be obtained by routine sequencing, or is available from publicly available databases.
  • an "isolated" antibody or binder has been purified from other components of the cell Contaminating components of a cell which may interfere with a diagnostic or therapeutic use are, for example, enzymes, hormones, or other peptidic or non-peptidic components of a cell an amino acid or binder which has been purified to more than 95% by weight, based on the antibody or binder (determined, for example, by Lowry method, UV-Vis spectroscopy or by SDS capillary gel electrophoresis), which has been purified to the extent that at least 15 amino acids of the amino terminus or an internal amino acid sequence can be determined or purified to homogeneity, the homogeneity being determined by SDS-PAGE under reducing or non-reducing conditions (the detection can be determined by Coomassie blue staining or preferably by silver staining).
  • a ⁇ ⁇ becomes normal ise prepared by one or more purification steps.
  • the term "specific binding” or “specific binding” refers to an antibody or binder that binds to a predetermined antigen / target molecule.
  • Specific binding of an antibody or binder typically describes an antibody or binding with an affinity of at least 10 "7 M (as Kd value, so preferably those with smaller Kd values than lO"'7 M), wherein the antibody or binder has at least two-fold higher affinity for the predetermined antigen / target molecule than for a non-specific antigen / target molecule (eg, bovine serum albumin, or casein) which is not the predetermined antigen / target molecule or a closely related antigen / target molecule.
  • a non-specific antigen / target molecule eg, bovine serum albumin, or casein
  • Antibodies specific for a cancer cell antigen may be prepared by those of ordinary skill in the art by methods known to those skilled in the art (such as recombinant expression) or may be purchased commercially (e.g., from Merck KGaA, Deustchland). Examples of known commercially available antibodies in cancer therapy are Erbitux® (Cetuximab, Merck KGaA), Avastin® (Bevacizumab, Roche) and Herceptin® (Trastuzumab, Genentech).
  • the antibody is produced recombinantly in CHO cells.
  • the compounds of the formula (i) represent a subgroup of the compounds of the formula (Ia).
  • Preferred subject matter of the invention are binder-active compound conjugates of the general formula (Ia) in which n is a number from 1 to 50,
  • AK for AK. or AK 2 represents
  • AK. for a binder (preferably an anti-C4.4a antibody) bound to the group G via a sulfur atom of the binder preferably an anti-C4.4a antibody bound to the group G via a sulfur atom of the binder
  • n is a number from 2 to 6
  • ## 5 denotes the point of attachment to the group G
  • L ' A is linear (C 2 -C 10) -alkanediyl.
  • R 33 is hydrogen, (C 1 -C 4) -alkylcarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl,
  • R 34 is hydrogen or methyl
  • R 29 is hydrogen or (C 1 -C 4) -alkyl
  • R 30 is hydrogen or (C 1 -C 4) -alkyl, or R 30 together with the atoms to which they are attached form a 5- or 6-membered heterocycle, R 31 is hydrogen or (Ci-G alkyl, R 32 is hydrogen or (Ci-C4) alkyl, or
  • R 3 'and R 3 together with the atoms to which they are attached form a 5- or 6-membered heterocycle
  • L ' B is linear (Ci-Cicj alkandivl, and wherein (Ci-Cio) alkanediyl may be substituted with 1 to 4 substituents independently selected from the group consisting of methyl, hydroxy and benzyl, and wherein two carbon atoms of the alkanediyl chain in 1, 2, 1, 3 or 1, 4 relation to each other, including the carbon atoms optionally between them can be bridged to a (Cs-Cej-cycloalkyl ring or a phenyl ring, for a bond or a group the formula
  • the point of attachment is L 1
  • the point of attachment is L 2 , O or NH.
  • L 3 is a bond or (C 2 -C 4 -alkanediyl.
  • L 4 represents a bond or a group of the formula
  • point of attachment to the carbonyl group is characterized. denotes the point of attachment to L 2 , is hydrogen or methyl.
  • R is hydrogen, (C 1 -C 4 ) -alkylcarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl,
  • Q 1 represents a 4- to 7-membered heterocycle
  • Q 2 is a 3- to 7-membered carbocycle or a 4- to 7-membered heterocycle
  • R 14 is hydrogen or (Ci-C 4 ) -alkyl
  • R ! 5 represents hydrogen or (C 1 -C 4 ) -alkyl
  • R 14 and R 13 together with the atoms to which they are attached form a 5- or 6-membered heterocycle
  • R 16 represents hydrogen or (C 1 -C 4 ) -alkyl
  • R 17 is hydrogen or (Ci-C 4 ) -alkyl, or
  • R 16 and R 17 together with the atoms to which they are attached form a 5- or 6-membered heterocycle
  • R 18 is hydrogen or (C 1 -C 4) -alkyl
  • R 19 represents hydrogen or the side group of a natural ⁇ -amino acid or its homologs or isomers
  • R 20 is hydrogen or (C 1 -C 4 ) -alkyl, or
  • R 21 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 22 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 23 represents (Ci-CVi-alkyl
  • R 24 is hydrogen or (C 1 -C 4) -alkyl
  • R 27 is hydrogen or C 1 -C -alkyl
  • R j6 represents hydrogen, (C 1 -C 4) -alkylcarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl,
  • R 37 is hydrogen or methyl
  • L 2 is linear (C 2 -C 10) -alkanediyl or a group of the formula where p is a number from 2 to 6,
  • ## 3 denotes the point of attachment to the group B
  • (C 2 -C 10) -alkanediyl having 1 to 4 substituents independently of one another can be substituted from the group consisting of methyl, hydroxy and benzyl, and where two carbon atoms of the alkanediyl chain are in 1, 2, 1, 3 or 1 , 4-relative to one another, including the optionally located between them Kohienstoffatome to a (C3-C6) -Cycloa31cyi ring or a phenyl ring may be bridged,
  • R 2 is Tsopropyl, isobutyl, ⁇ -butyl, tert-butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 1-phenyl ethyl, diphenylmethyl, 1H-lxiidazol-4-ylmethyl or 1H-indol-3-ylmethyl, or
  • # 5 denotes the point of attachment with the Carbonyi group, the ring A with the NO group contained therein for a mono- or bicyclic, optionally substituted heterocycle of the formula
  • R ' is hydrogen, hydroxy or benzyloxy, is hydrogen or methyl, isopropyl, isobutyl, sec-butyl, tert-butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 1 - Phenyl ethyl, diphenylmethyl, 1H-imidazol-4-ylmethyl or 1/7-indol-3-ylmethyl,
  • # 8 identifies the point of attachment to the group T 1 .
  • R ? represents hydrogen, methyl, ethyl, w-propyl, tert-butyl, benzyl or adamantylmetyl
  • R 8 is hydrogen or methyl
  • R 9 is hydrogen, methyl, ethyl, propyl or benzyl, or
  • R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle
  • R i0 is benzoyl.
  • R u for benzyl which may be substituted in the phenyl group with methoxyearbonyi or carboxyl, is hydrogen, methyl or a group of the forms! stands in which
  • # 9 identifies the point of attachment with -CHC (R 26 ) -T 2 ,
  • R '' ' is phenyl, which may be substituted by methoxyearbonyi, carboxyl or a group of the formula -S (O):> OH,
  • R is phenyl which may be substituted with methoxyearbonyi or carboxyl
  • R 26 is hydrogen or hydroxy
  • T 2 is pbenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl, R 35 is methyl or hydroxy, and their salts, solvates and solvates of the salts.
  • Preferred subject matter of the present invention are binder-active compound conjugates of the general formula (Ia) as indicated above, in which n is a number from 1 to 50,
  • AK for AK or ⁇ K wherein for a binder (preferably a anfi-C4.4a Amik bound via a sulfur atom of the binder to the group G, AK 2 for a binder (preferably an anti-C4.4a antibody) which is bound to the group G via a nitrogen atom of the binder,
  • n is a number from 2 to 6.
  • ## 1 denotes the point of attachment to the gib G
  • L iA is linear (C-2-Cio) -alkanediyl
  • R 33 is hydrogen, (C 1 -C 4) -alkylcarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl,
  • R 34 is hydrogen or methyl
  • R 29 is hydrogen or (C 1 -C 4) -alkyl
  • R 30 is hydrogen or (C 1 -C 4) -alkyl, or R 30 together with the atoms to which they are attached form a 5- or 6-membered heterocycle, R 31 is hydrogen or (Ci-G alkyl, R 32 is hydrogen or (Ci-C4) alkyl, or
  • R 31 and R 3 together with the atoms to which they are attached form a 5- or 6-membered heterozygus
  • L lB is linear (Ci-Ciöj alkanediyl, and wherein (Ci-Cio) -Alkandiyi may be substituted with 1 to 4 substituents independently selected from the group consisting of methyl, Hydroxv and benzyl, and wherein two carbon atoms of the alkanediyl chain in 1, 2, 1, 3 or 1, 4 relative to each other, with the inclusion of any carbon atoms between them may be bridged to a (Cs-Cej-Cycioalkyl ring or a phenyl ring, a bond or a group of Fonnel
  • L 3 represents a bond or (C 1 -C 6 -alkanediyl
  • L 4 represents a bond or a group of the formula
  • R 25 is hydrogen or methyl
  • R 28 is hydrogen, (C 1 -C 4) -alkylcarbonyi, tert-butyloxycarbonyl or benzyloxycarbonyl,
  • Q 1 is a 4- to 7-membered heterocycle
  • Q 2 is a 3- to 7-membered carbocycle or a 4- to 7-membered heterocycle
  • R 14 is hydrogen or (C 1 -C 4 -alkyl
  • R 15 is hydrogen or (Ci-C 4 ) -alkyl, or
  • R 14 and R 13 together with the atoms to which they are attached form a 5- or 6-membered heterocycle
  • R 16 is hydrogen or
  • R 17 is hydrogen or (C 1 -C 4 ) -alkyl, or
  • R 18 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 19 is hydrogen or the side group of a natural ⁇ -amino acid or its
  • R 20 is hydrogen or (C 5 -C) alkyl, or
  • R 2 ' is hydrogen or (C 1 -C 4) -alkyl
  • R 22 is hydrogen or (Ci-C4) alkyl, or
  • R zl and R z2 together with the atoms to which they are attached form a 3- to 7-membered carbocycle
  • R 23 is (C 1 -C 4 ) -alkyl
  • R 24 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 27 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 36 represents hydrogen, (C 1 -C 4 ) -alkylcarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl,
  • R ,? is hydrogen or methyl
  • ## 3 denotes the point of attachment to the group B
  • R ! is hydrogen or methyl
  • R 1 is isopropyl, isobutyl, sec-butyl, fö / t-butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 1-phenyl ethyl, diphenylmethyl, 1H-imidazol-4-ylmethyl or 1H-indol-3-ylmethyl, or
  • # 4 denotes the point of attachment to the adjacent nitrogen atom
  • # 5 denotes the point of attachment to the carbonyl group
  • ring A contains the NO group contained therein for a monocyclic or bicyclic, optionally substituted heterocycle of the formula
  • R 6 is hydrogen, hydroxy or benzyloxy
  • R J is hydrogen or methyl
  • R 4 is isopropyl, isobutyl, sec-butyl, tert-butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 1-phenylethyl, Diphenylmethyl, 1H-imidazol-4-ylmethyl or 1/7-indol-3-ylmethyl, or
  • R 7 is hydrogen, methyl, ethyl, w-propyl, tert-butyl, benzyl or adamantylmethyl,
  • R 8 is hydrogen or methyl
  • R 9 is hydrogen, methyl, ethyl, w-propyl or benzyl, or
  • R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle
  • R i0 is benzoyl
  • R ' 1 for benzyl which may be substituted in the Phenyignippe with methoxycarbonyl or carboxyi, is hydrogen, methyl or a group of the formula
  • R 12 is phenyi which may be substituted by methoxycarbonyl, carboxy or a group of the formula -S (O) 20H,
  • R ' 3 is phenyi which may be substituted with methoxycarbonyl or carboxyi
  • R zo is hydrogen or hydroxy
  • T 2 is phenyi, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl, R 35 is methyl or hydroxy, and their salts, solvates and solvates of the salts.
  • Preferred subject matter of the invention are B in the active substance Koniugate of the general formula (Ia), in which n is a number from 1 to 20, AK for AK, or AK 2 is
  • AK- for an antibody or an antigen-binding antibody fragment which binds to C4,4a and is bound to the group G via the sulfur atom of a cysteine residue of the binder
  • AK.2 for an antibody or an antigen sees binding anii Economicsfragrneni which binds to C4.4a and is bound via the NH side group of a lysine residue of the binder to the group G
  • AK AKi
  • n is a number from 2 to 6
  • L iA stands for linear (CVCej alkandiy!
  • ## 7 denotes the point of attachment with the carbonyl group
  • ## 8 denotes the point of attachment to LIB
  • R J is hydrogen, methylcarbonyl or tert-butyloxycarbonyl
  • R 34 is hydrogen or methyl
  • R 29 is hydrogen
  • R 30 is hydrogen
  • R 31 is hydrogen or methyl
  • R 32 is hydrogen or methyl
  • L 3 is a bond or ethane-l, 2-diyl
  • R 25 is hydrogen or methyl
  • R 28 is hydrogen, methylcarbonyl or iert.-butyloxycarbonyl
  • Q ' is a 4- to 7-membered heterocycle
  • R 14 is hydrogen
  • R 15 is hydrogen
  • R 16 is hydrogen or methyl
  • R 17 is hydrogen or methyl
  • R 18 is hydrogen
  • R 19 is hydrogen, methyl, propan-2-yl, 2-methylpropan-1-yl or 1-methylpropan-1-yl,
  • R 20 is hydrogen or methyl
  • R 2i is hydrogen or methyl
  • R 2 is hydrogen or methyl, or
  • R 24 is hydrogen or methyl
  • R 27 is hydrogen
  • R 36 is hydrogen, methylearbonyl or tert-butyloxycarbonyl
  • R looks for hydrogen or methyl, or R 36 and R 37 , together with the atoms to which they are attached form PyiTolidinring, linear (C 2 -C 6) alkanediyl or a group of the formula where p is a number from 2 to 6,
  • ## 3 denotes the point of attachment to the group B
  • R 1 is hydrogen
  • R 2 is 1-hydroxyethyl, benzyl, 4-hydroxybeiizyl, 1-phenylethyl or 1H-indol-3-ylmethyl, or
  • # 4 identifies the linkage site with the adjacent nitrogen atom
  • # 5 identifies the linkage site with the carbonyl group, the ring A with the NO moiety contained therein for a monocyclic or bicyclic, optionally substituted heterocycle of the formula
  • # ö denotes the point of attachment to the carbonyl group
  • R 6 represents hydrogen, hydroxyl or benzyloxy
  • R 3 is hydrogen
  • R 4 is 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-ylmethyl.
  • R 7 is hydrogen, methyl, ethyl, w-propyl, tert-butyl, benzyl or adamantylmethyl,
  • R 8 is hydrogen or methyl
  • R 9 is hydrogen, methyl, ethyl, w-propyl or benzyl, or
  • R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle
  • R i0 is benzoyl
  • R ' 1 for benzyl which may be substituted in the phenyl group with methoxycarbonyl or carboxyi, is hydrogen, methyl or a group of the formula
  • R 12 is phenyi, that with methoxycarbonyl, carboxyi or a group of the forms! -S (0) 20H can be substituted,
  • R ' 3 is phenyi which may be substituted with methoxycarbonyl or carboxyi
  • R zo is hydrogen or hydroxy
  • T 2 is phenyi, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl, R 35 is methyl or hydroxy, and their salts, solvates and solvates of the salts.
  • Preferred subject matter of the present invention are binder-active compound conjugates of the general formula (Ia) as indicated above, in which n represents a number from 1 to 20, AK represents AK, or AK 2 represents
  • AK- for an antibody or an antigen-binding antibody fragment which binds to C4,4a and is bound to the group G via the sulfur atom of a cysteine residue of the binder
  • m is a number from 2 to 6, which indicates the point of attachment to the group G,
  • V stands for a bond
  • L 6 represents a bond or a group of the formula
  • ## 7 denotes the point of attachment with the carbonyl group
  • ## 8 denotes the point of attachment to LIB
  • R J is hydrogen, methylcarbonyl or tert-butyloxycarbonyl
  • R 34 is hydrogen or methyl
  • R 29 is hydrogen
  • R 30 looks for hydrogen
  • R 31 is hydrogen or methyl
  • R 32 is hydrogen or methyl
  • L 1B is linear (C 2 -C 6) -alkanediyl
  • L 3 is a bond or ethane-l, 2-diyl
  • L 4 represents a bond or a group of the formula
  • R 25 is hydrogen or methyl
  • R 28 is hydrogen, methylcarbonyl or tert-butyloxycarbonyl
  • Q 1 is a 4- to 7-membered heterocycle
  • R 14 is hydrogen
  • R ! 5 is hydrogen
  • R 16 is hydrogen or methyl
  • R ' 7 is hydrogen or methyl
  • R 19 is hydrogen, methyl, propan-2-yl, 2-methylpropan-1-yl or 1-methylpropan-1-yl,
  • R 20 is hydrogen or methyl
  • R 21 is hydrogen or methyl
  • R 22 is hydrogen or methyl
  • R 24 is hydrogen or methyl
  • R 27 is hydrogen
  • R 36 is hydrogen, (C 1 -C 4) -alkylcarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl, R 37 is hydrogen or methyl.
  • R 1 is hydrogen
  • R 2 is 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-ylmethyl, or
  • # 4 identifies the linkage site with the adjacent nitrogen atom
  • # 5 identifies the linkage site with the carbonyl group, the ring A with the NO moiety contained therein for a monocyclic or bicyclic, optionally substituted heterocycle of the formula
  • # ö denotes the point of attachment to the carbonyl group
  • R 6 represents hydrogen, hydroxyl or benzyloxy
  • R 3 is hydrogen
  • R 4 is 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-ylmethyl.
  • R 7 is hydrogen, methyl, ethyl, w-propyl, tert-butyl, benzyl or adamantylmethyl,
  • R 8 is hydrogen or methyl
  • R 9 is hydrogen, methyl, ethyl, w-propyl or benzyl, or
  • R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle
  • R i0 is benzoyl
  • R ' 1 for benzyl which may be substituted in the Phenyigi'uppe with methoxycarbonyl or carboxyi, is hydrogen, methyl or a group of the formula
  • R 12 is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula -S (0) 2 0H,
  • R ' 3 is phenyl which may be substituted by methoxycarbonyl or carboxyl,
  • R zo is hydrogen or hydroxy
  • T 2 represents phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl
  • R J5 is methyl or hydroxy, and their salts, solvates and solvates of the salts.
  • Preferred object of the invention are binder active ingredient Koniugate of the general formula (fa), in which n is a number from 1 to 10, AK for AKi or AK 2 is
  • AK- for an antibody containing the six CDR sequences of the antibody B0I -3, B01-10, M31-B01 or D02-6, the variable light and variable heavy chain of the antibody B01-3, B01-10, M31 - B01 or D02-6 or the light and heavy chain of the antibody B01-3, B01 -10, M31-B01 or D02-6, which is bound via the sulfur atom of a cysteine residue of the binder to the group G,
  • L 1 represents a bond, linear (CVChj-alkanediyl, a group of formula where m is a number of 2 or 3,
  • ## 5 denotes the point of attachment to the group G
  • L 3 is a bond or ethane-l, 2-diyl.
  • L 4 represents a bond or a group of the formula
  • R 25 is methyl
  • Q 1 is piperidine-1, 4-diyl, R 16 is hydrogen or methyl, R ! 7 is hydrogen or methyl, or
  • R 2 is hydrogen or meth l
  • R 22 is hydrogen or methyl
  • R 23 is methyl
  • R 24 is hydrogen
  • R 3! is hydrogen, methylcarbony] or tert-butyloxycarbonyl
  • R 37 is hydrogen or methyl
  • L 2 is linear (Ci-Cel-alkanediyl or a group of the formula
  • ## 3 denotes the point of attachment to the group B
  • R 1 is hydrogen
  • R is 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-yl-methyl, or 1 and R 2 together with the carbon atom to which they are attached form a
  • # 5 denotes the point of attachment with the carbonyl group, the ring A with the NO group contained therein for a mono- or bicyclic, optionally substituted heterocycle of the formula wherein the point of attachment to the carbonyl group is hydrogen, hydroxy or benzyloxy.
  • R ! stands for hydrogen
  • R 4 is benzyl, 4-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-ylmethyl, above
  • R ' is hydrogen, methyl, ethyl, r-propyl, tert-butyl, benzyl or adamantvlmethvl
  • R 8 is hydrogen or methyl
  • R 9 is hydrogen, methyl, ethyl, propyl or benzyl
  • R 1 is benzyl which may be substituted in the phenyl group by methoxyearbonyl or carboxyl,
  • R 5 is hydrogen, methyl or a group of the formula stands in which
  • # 9 identifies the linkage position with -CHCEfePhenyl
  • R ' 2 stands for Phenvl, which with methoxyearbonyl, carboxyl or a group of the forms! -S (0) 2 0H can be substituted
  • R is phenyl which may be substituted with methoxyearbonyl or carboxyl
  • R is methyl or hydroxy, and their salts, solvates and solvates of the salts.
  • Preferred subject matter of the present invention are binder-active compound conjugates of the general formula (Ia) as indicated above, in which n is a number from 1 to 10,
  • AK for AK. or AK 2 represents
  • AKi for an antibody comprising the six CDR sequences of the antibody B01-3, B01-10, M31-B01 or D02-6, the variable light and variable heavy chain of the antibody B01-3, B01-10, M31-B01 or D02-6 or the light and heavy chain of the antibody B01-3, B01 -10, M31 -B01 or D02-6, which is bound via the Scliwefeiatom a Cvstein residue of the binder to the group G
  • L 3 looks for a bond or ethane-1, 2-diyl
  • R 25 is methyl
  • R 28 is hydrogen, methylcarbonyl or tert-butyloxycarbonyl, Q 1 is piperidin-1,4-diyl,
  • R ! 6 is hydrogen or methyl
  • R 17 is hydrogen or methyl
  • R 2i is hydrogen or methyl
  • R 22 is hydrogen or methyl
  • R i4 is hydrogen, linear (Ca-CeVAikandiyl or a group of the formula where p is a number from 2 to 6,
  • R ' is hydrogen
  • R z is 1-hydroxyethyl, benzyl, ⁇ -hydroxybenzyl, 1-phenylethyl or 1/7-indol-3-yl methvl, ocier
  • R is hydrogen, hydroxy or benzyloxy
  • R 3 is hydrogen
  • R 4 is benzyl, 1-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-ylmethyl, or R J and R 4 together with the carbon atom to which they are attached form a (15,2R) -2-phenylcyclopropane-1,1-diyl group of the formula
  • R 7 is hydrogen, methyl, ethyl, propyl, tert. Butyl, benzyl or adamantylmethyl,
  • R 8 is hydrogen or methyl
  • R 9 is hydrogen, methyl, ethyl, propyl or benzyl
  • R ' 1 for benzyl which may be substituted in the phenyl group with methoxycarbonyl or carboxyi, is hydrogen, methyl or a group of the formula in which the linking parts are denoted by -CHCtbPhenyl, is phenyl which may be substituted by methoxycarbonyl, carboxy or a group of the formula -SiOj OH, R ' 3 is phenyl which may be substituted by methoxy-carbonyl or carboxyl,
  • R 35 is methyl or hydroxy, and their salts, solvates and solvates of the salts.
  • Preferred subject matter of the present invention are binder-active compound conjugates of general formula (Ia) as indicated above, in which n is a number from 1 to 10,
  • AK stands for AK 2 , where
  • AK.2 for an antibody comprising the six CDR sequences of the antibody BO1-3, B01-10, M31-B01 or D02-6, the variable light and variable heavy chain of the antibody B01-3, B01-10, M31 B01 or D02-6 or the light and heavy chain of the Anügropers BOI-3, B01 -10, M31-B01 or D02-6 comprises, which is bound via the NH side group of a lysine residue of the binder to the group G. .
  • G is carbonyl
  • B is a bond, linear (Ca-Cej alkanediyl or a group of the formula
  • R 1 is hydrogen
  • R 2 is benzyl or 1H-indol-3-ylmethyl
  • # 5 denotes the point of attachment to the carbonyl group, the ring A with the NO group contained therein for a mono- or bicyclic, optionally substituted Heierocyclus of the formula
  • R 3 is hydrogen
  • R 4 is benzyl or 1H-indol-3-ylmethyl, or
  • R 7 is hydrogen, methyl, ethyl, w-propyl, tert-butyl, benzyl or adamantylmethyl,
  • R 8 is hydrogen
  • R 9 is hydrogen or benzyl
  • R is methyl. and their salts, solvates and solvates of the salts.
  • Preferred subject matter of the present invention are binder-active compound conjugates of the general formula (Ia) as indicated above, in soft n is a number from 1 to 10,
  • AK stands for AK2, where
  • G is carbonyl
  • V stands for a bond
  • ## 3 denotes the point of attachment to the group B
  • R 2 is 4-hydroxybenzyi or 1 // - Tndol-3-ylmethyl, or
  • # 5 denotes the linking moieties with the carbonyl group, the ring A with the NO moiety contained therein for a mono- or bicyclic, optionally substituted heterocycle of the formula
  • R 3 is hydrogen
  • R 4 is 4-hydroxybenzyl or 1H-indol-3-ylmethyl, or R J and R 4 together with the carbon atom to which they are attached form a (1S, 2R) -2-phenylcyclopropane ⁇ , 1-diyl group of the formula
  • R 7 is hydrogen, methyl, F, ethyl, propyl, tert-butyl, benzyl or adamantylmethyl,
  • R 8 is hydrogen
  • R 9 is hydrogen or benzyl
  • R 35 is methyl, and their salts, solvates and solvates of the salts.
  • Preferred subject matter of the present invention are binder-active compound conjugates of the general formula (Ia) as indicated above, in which n is a number from 1 to 10,
  • AK for an antibody containing the six CDR sequences of the antibody BOl -3, B01-10, M31-B01 or D02-6, the variable light and variable heavy chain of the antibody Antibody B01-3, BOI -10, M31-B01 or D02-6 or the light and heavy chain of the antibody B01-3, BOI-10, M31-B01 or D02-6, which is linked via the sulfur atom of a cysteine Restes of the binder is bound to the group G, for a group of the formula
  • # 2 denotes the point of attachment to the group L ', a bond, linear (C3-C5) alkanediyl or a group of the formula where m is a number of 2 or 3,
  • L 3 is a bond or ethane-1, 2-diyl
  • L 4 is a bond or a group of the formula
  • R z8 is hydrogen, methylcarbonyl or tert-butyloxycarbonyl, R li! is hydrogen or methyl,
  • R 1 ' is hydrogen or methyl
  • R 1 is hydrogen
  • R 2 is benzyl or 1H-indol-3-ylmethyl
  • # 5 denotes the point of attachment to the carbonyl group, the ring A with the NO group contained therein for a mono- or bicyclic, optionally substituted Heierocyclus of the formula
  • R 3 is hydrogen
  • R 4 is benzyl or 1H-indol-3-ylmethyl
  • R is hydrogen
  • R 9 is hydrogen or benzyl
  • R 35 is methyl, and their salts, solvates and solvates of the salts.
  • Preferred subject matter of the present invention are binder-active conjugates of the general Fonnei (la) as indicated above, in soft n is a number from 1 to 1 0,
  • AK stands for AKi, where
  • AKi for an antibody containing the six CDR sequences of the antibody B01-3, BOi-K ) , M31-B01 or D02-6, the variable light and variable heavy chain of the antibody B01-3, B01 -10, M31 - B01 or D02-6 or the light and heavy chain of the antibody B01 -3, BOl -10, M31-B01 or D02-6 urnankt, which is bound via the sulfur atom of a cysteine residue of the binder to the group G.
  • G is a group of the formula
  • tt denotes the point of attachment with the group L 1 , for a bond, linear (C 3 -C 5) -alkanediyl or a group of the formula where m is a number of 2 or 3,
  • ## 1 denotes the point of attachment to the group G which identifies the point of attachment to the group B.
  • (C 3 -C 5) -alkanediyl can be substituted by ⁇ or 2 substituents methyl, for a bond or a group of the formula where the point of attachment is labeled L ', the point of attachment is labeled L 2 ,
  • L- is a bond or ethane-l, 2-diyl, a bond or a group of the formula
  • R 2S is hydrogen, methylcarbonyl or tert-butyloxycarbonyl
  • R li! is hydrogen or methyl
  • R 17 is hydrogen or methyl
  • i denotes the point of attachment to the group B
  • ⁇ denotes the point of attachment to the nitrogen atom
  • R 1 is hydrogen
  • R 2 is 4-hydroxybenzyl or 1H-indol-3-ylmethyl, or
  • R 3 is hydrogen
  • R 4 is 4-hydroxybenzyl or 1H-indol-3-ylmethyl, or
  • R 7 is hydrogen, methyl, ethyl, w-propyl, tert. Is butyl, benzyi or adamantylmethyl,
  • R 8 is hydrogen, R is hydrogen or benzyl
  • R 35 is methyl, and their salts, solvates and solvates of the salts.
  • Another object of the present invention are compounds of the formula (XXXa)
  • ## 5 denotes the point of attachment to the group G
  • A is linear (C 2 -C 10) -alkanediyl
  • R 29 is hydrogen or (Ci-C4) alkyl
  • R J0 is hydrogen or (Ci-C4) -Alk, or
  • R 29 and R 30 together with the atoms to which they are attached form a 5- or 6-membered heterocycle
  • R J1 is hydrogen or (Ci-C4) -Alk l,
  • R 32 is hydrogen or (Ci-C- alkyl, or
  • R 31 and R 3i together with the atoms to which they are attached form a 5- or 6-membered heterocycle
  • L iB is linear (C 2 -C 10) -alkanediyl, and wherein (C 1 -C 10) -alkanediyl may be substituted with 1 to 4 substituents independently selected from the group of methyl, hydroxy and benzyl, and wherein two carbon atoms of the alkanediyl Chain in 1, 2, 1, 3, or 1, 4 relation to each other, including the carbon atoms optionally between them can be bridged to a (C3-Ce) -cycloalkyl ring or a phenyl ring, for a bond or a group of the formula
  • L 3 is a bond or (C 2 -C 4 ) -alkanediyl, L 4 is a bond,
  • Q 2 is a 3- to 7-membered carbocycle or a 4- to 7-membered heterocycle
  • R 14 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 15 is hydrogen or (C 5 -C) -alkyl
  • R 14 and R 15 together with the atoms to which they are attached form a 5- or 6-membered heterocycle
  • R ! 6 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 17 is hydrogen or (Ci-C 4 ) -alkyl, or R 16 and R 17 together with the atoms to which they are attached form a 5- or 6-membered heterocycle,
  • R 18 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 19 is hydrogen or the side group of a natural ⁇ -amino acid or its homologs or isomers
  • R 20 is hydrogen or (C 1 -C 4 ) -alkyl, or
  • R 21 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 22 is hydrogen or (Ci-CVi-alkyl, or
  • R i and R 2 together with the atoms to which they are attached form a 3- to 7-membered carbocycle, R 23 is (C 1 -C 4 ) -alkyl,
  • R 24 is hydrogen or (C 1 -C 4) -alkyl
  • R 27 is hydrogen or (C 1 -C 4) -alkyl, linear (C 2 -C 10) -alkanediyl or a group of the formula where p is a number from 2 to 6,
  • ## 4 denotes the point of attachment to the nitrogen atom, wherein (C 2 -C 10) -alkanediyl may be substituted with 1 to 4 substituents independently selected from the group of methyl, hydroxy and benzyl, and wherein two carbon atoms of the alkanediyl chain in 1,2-, 1, 3 or 1,4 Relation to each other, with the inclusion of any intervening between carbon atoms carbon atoms to a (Cj-Ce Cyeloa kyl ring or a phenyl ring may be bridged, for a group of the formula
  • # J denotes the point of attachment to the nitrogen atom
  • R 1 is hydrogen or methyl
  • R 2 isopropyl, isobutyl, sec-butyl, tert-butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 1-phenyl ethyl, diphenylmethyl, 1H-imidazol-4-ylmethyl or 1H-indol-3-ylmethyl, or
  • # 5 denotes the point of attachment with the Carbonyi group, the ring A with the -0- moiety contained therein for a mono- or bicyclic, optionally substituted heterocycle of the formula
  • R 6 is hydrogen, hydroxy or benzyloxy
  • R 3 is hydrogen or methyl
  • R 4 isopropyl, isobutyl, sec-butyl, tert-butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzene 1, 1-phenyl ethyl, diphenylmethyl, 1H-imidazol-4-ylmethyl or 1H-indol-3-ylmethyl, or
  • R 7 is hydrogen, methyl, ethyl, propyl, f-tert-butyl, benzyl or adamantylmethyl,
  • R s is hydrogen or methyl
  • R 9 is hydrogen, methyl, ethyl, propyl or benzyl, or
  • R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle
  • R '° is benzoyl
  • R ' 1 for benzyl which may be substituted in the phenyl group with methoxycarbonyl or carboxyl, is hydrogen, methyl or a group of the formula
  • # 9 denotes the point of attachment with -CHC (R 26 ) ⁇ T
  • R 12 is phenyl which may be substituted by methoxycarbonyl, carboxyl or a group of the formula ⁇ S (0) 2 0H,
  • R ' 3 is phenyl which may be substituted by methoxycarbonyl or carboxyl
  • R z6 is hydrogen or hydroxy
  • T 2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmethyl,
  • R 35 is methyl or hydroxy, and their salts, solvates and solvates of the salts.
  • Preferred subject matter of the present invention are compounds of the formula (XXXa) as stated above, in which
  • Cys stands for a cy- stone radical which is linked via the sulfur atom of the side chain via a carbon atom of the succinimide
  • ## 1 denotes the point of attachment to the group G
  • L lA is linear (Ci-Cej alkanediyl
  • ## 5 denotes the point of attachment to the group L ' A
  • ## 6 denotes the point of attachment to the group L' B
  • L 5 represents a bond
  • Sets L 6 for a bond
  • R ⁇ 9 is hydrogen
  • R 30 is hydrogen
  • R 3 ' is hydrogen or methyl
  • R 32 is hydrogen or methyl
  • L iB is linear (C 2 -C 6) -alkanediyl
  • L 3 is a bond or ethane, 2-diyl
  • R 14 is hydrogen
  • R l3 is hydrogen
  • R ! 6 is hydrogen or methyl
  • R 17 is hydrogen or methyl
  • R 16 and R i 7 together with the atoms to which they are attached form piperazinyl ring, R 23 is methyl,
  • R 24 is hydrogen or methyl
  • L 2 is linear (C -C -alkanediyl or a group of Fonriei where p is a number of 2 or 3
  • ## 3 denotes the point of attachment to the group B
  • R 2 is 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-yl methyl, or R 1 and R 2 together with the carbon atom to which they are attached form a (1S, 2R) -2-phenylcyclopropane-1,1-diyl group of the formula
  • R 3 is hydrogen, 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 1-phenyietliyl or 1H-indole-methvl sees, oaer
  • R 7 is hydrogen, methyl, ethyl, w-propyl, terr. Butyl, benzyl or adamantylmethyl,
  • R 8 is hydrogen or methyl
  • R 9 is hydrogen, methyl, ethyl, w-propyl or benzyl, or
  • R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle
  • R i0 is benzoyl
  • R ' 1 for benzyl which may be substituted in the Phenylgnippe with Metlioxycarbonvi or Carboxyi, is hydrogen, methyl or a group of the formula stands in which # 9 identifies the point of attachment with -CHCFfaPhenyl,
  • R 12 is phenyl represented by methoxycarbonyl, carboxyi or a group of the formula -S (O) ? .OH can be substituted,
  • R is phenyl which may be substituted by methoxycarbonyl or carboxyi
  • R 35 is methyl or hydroxy, and their salts, solvates and solvates of the salts.
  • Preferred subject matter of the present invention are compounds of formula (XXXa) as indicated above, in which Cys is a cysteine radical which is bonded via the sulfur atom of the side chain via a carbon atom of the succinimide
  • L ' is a bond or linear (CVC ft KAJkandiyl
  • L 3 is a bond
  • L 4 is a bond
  • R i 6 is hydrogen or methyl
  • R 17 is hydrogen or methyl
  • L 2 is linear (C 2 -C 6) -alkanediyl or a group of the formula sees, where stands for a number of 2 or 3, the point of attachment with the ⁇ B indicates.
  • R 1 is hydrogen
  • R 2 is benzyl or 1H-indol-3-ylmethyl, or
  • # 5 denotes the point of attachment with the carbonyl group, the ring A with the NO group contained therein for a mono- or bi-cyclic, optionally substituted heterocycle of the formula
  • # 6 denotes the linking moieties with the carbonyl group
  • R 3 is hydrogen
  • R 4 is benzyl or 1 H-indol-3-ylmethyl
  • R 8 is hydrogen
  • R y is hydrogen
  • R 35 is methyl, and their salts, solvates and solvates of the salts.
  • Cys stands for a cysteine residue that is linked via the sulfur atom of the side chain via a carbon atom of the succinimide
  • L stands ! is a bond or linear (C 2 -C 6) -alkanediyl
  • L 3 is a bond
  • R 16 is hydrogen or methyl
  • R '' is hydrogen or methyl, linear (C 2 -C 6) alkanediyl or Gmppe of the formula where p is a number of 2 or 3,
  • ## 3 denotes the point of attachment to the group B
  • # 3 denotes the point of attachment with the nitrogen atom
  • R 1 is hydrogen
  • R 2 is 4-hydroxybenzyl or 1H-indol-3-ylmethyl, or
  • # s denotes the point of attachment to the carbonyl group, the ring A with the N-0 -group contained therein for a mono- or bicyclic, optionally substituted heterocycle of the formula
  • R 3 is hydrogen, is 4-hydroxybenzyl or 1H-indol-3-ylmethyl, or
  • R 7 is hydrogen
  • R 8 is hydrogen, R is hydrogen,
  • R 35 is methyl
  • Another object of the present invention are compounds of formula (XXXI)
  • L ' is a bond, linear (i-Cio) alkandyl, a group of the formula stands, where
  • n is a number from 2 to 6
  • ## 1 denotes the point of attachment to the group G
  • A is linear (C 2 -C 10) -alkanediyl
  • R 29 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 30 is hydrogen or (C 1 -C 4) -alkyl, or
  • R 29 and R j0 together with the atoms to which they are attached form a 5- or 6-membered heterocycle
  • R 31 is hydrogen or (C 1 -C 4 -alkyl
  • R J2 is hydrogen or (Ci-CO-alkyl, or
  • R 1 and R 3 together with the atoms to which they are attached form a 5- or 6-membered heterocycle
  • L lB is linear (C 2 -C 10) -alkanediyl, and wherein (C 1 -C 10) -alkanediyl may be substituted with 1 to 4 substituents independently selected from the group of methyl, hydroxy and benzyl, and wherein two carbon atoms of the alkanediyl chain in 1, 2, 1, 3 or 1, 4 relative to each other, including the optionally present between ilinen carbon atoms to a (Cs-CeVCycloalkyl ring or a phenyl ring may be bridged, for a bond or a group of the formula
  • Q 1 is a 4- to 7-membered heterocycle
  • Q 2 is a 3- to 7-membered carbocycle or a 4- to 7-membered heterocycle
  • R ! 8 for hydrogen or R 19 is hydrogen or the side group of a natural ⁇ -amino acid or its
  • R 20 is hydrogen or (C 1 -C 4 ) -alkyl, or
  • R 2! is hydrogen or (C 1 -C 4 ) -alkyl
  • R 22 is hydrogen or (C 1 -C 4 ) -alkyl, or R zl and R z2 together with the atoms to which they are attached form a membered carbocycle,
  • R 27 for hydrogen or stands for linear (C2-Ciü) alkanediyl or for a group of the formula where p is a number from 2 to 6,
  • ## 3 denotes the point of attachment to the group B
  • (C 2 -C 10) -alkanediyl may be substituted with 1 to 4 substituents independently selected from the group consisting of methyl, hydroxy and benzyl, and wherein two carbon atoms of the alkanediyl chain are substituted in 1, 2, 1, 3 or 1, 4 Relation to each other, including the carbon atoms optionally between them can be bridged to a (Ca-Chj-cycloalkyl ring or a phenyl ring, for a group of formula
  • R ! is hydrogen or methyl
  • R z is isopropyl, isobutyl, .yec-butyl, te; ⁇ -butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyi, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 1-phenylethyl, diphenylmethyl, 1H-imidazol-4-ylmethyl or 1H- Indol-3-ylmethyl, or
  • # 5 denotes the point of attachment with the carbonyl group, the ring A with the N-0 group contained therein for a mono- or bicyclic, optionally substituted Ileterocyclus of Fonnel
  • R 6 is hydrogen, hydroxy or benzyloxy
  • R ! is hydrogen or methyl
  • R 4 is isopropyl, isobutyl, .sea-butyl, te; ⁇ -butyl, phenyl, benzyl, 1-hydroxyethyl, 4-hydroxybenzyl, 4-hydroxy-3-nitrobenzyl, 4-hydroxy-3-aminobenzyl, 1-phenylethyl, diphenylmethyl, 1H-imidazol-4-ylmethyl or 1H- Indol-3-ylmethyl, or
  • R 8 is hydrogen or methyl
  • R 9 is hydrogen, methyl, ethyl, n-propyl or benzyl, or R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle,
  • R 10 is benzoyl
  • R 1 is benzyl, which may be substituted in the phenyl group with methoxyearbonyl or carboxyi, is hydrogen, methyl or a group of the formula stands in which
  • # 9 identifies the point of attachment with -CHC (R 26 ) -T 2 ,
  • R i2 is phenyl which may be substituted by methoxyearbonyl, carboxyi or a group of the formula -S (0) 2 0H. is phenyl which may be substituted by methoxyearbonyl or carboxyi,
  • R i6 is hydrogen or Hydroxv.
  • T 2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmetiiyl,
  • R 35 is methyl or Hydroxv, and their salts, solvates and solvates of the salts.
  • Preferred subject matter of the present invention are compounds of the formula (XXXI) as indicated above, in which
  • L 1 represents a bond, linear (C 2 -C 6) alkanediyl or a group of the formula where m is a number of 2 or 3, ## 1 denotes the point of attachment to the group G,
  • R 18 is hydrogen
  • R 19 is methyl, propan-2-yl, 2-methylpropan-1-yl or 1-methylpropan-1-yl
  • R 20 is hydrogen or (C 1 -C 4 ) -alkyl, or
  • R 21 is hydrogen or methyl
  • R 22 is hydrogen or methyl
  • R 2i and R 22 together with the atoms to which they are attached form a cyclopropyl ring, R 2 'is hydrogen or methyl, linear (C 2 -C 6) alkanediyl or a group of the formula
  • ## 3 denotes the linking item with group B
  • (C-2-Cio) -alkanediyl may be substituted with 1 or 2 substituents methyl, and wherein two carbon atoms of the alkanediyl chain in 1,4-relation to each other, including the carbon atoms optionally between them, be bridged to a phenyl-Rtng can, for a group of formula
  • # J denotes the point of attachment to the nitrogen atom
  • R 1 is hydrogen
  • R 2 is 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 1-phenylethyl or 1H-indol-3-yl-methyl. or R 1 and R 2 together with the carbon atom to which they are attached form a (1S, 2R) -2-phenylcyclopropane-1,1-diyl group of the formula
  • R 3 is hydrogen, for 1-hydroxy xyethyl, benzyl, 4-hydroxybenzyl, 1-phenylethyl or lH indole methvl sees, oaer
  • R 7 is hydrogen, methyl, ethyl, w-propyl, terr. Butyl, benzyl or adamantylmethyl,
  • R 8 is hydrogen or methyl
  • R 9 is hydrogen, methyl, ethyl, w-propyl or benzyl, or
  • R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle
  • R i0 is benzoyl
  • R ' 1 for benzyl which may be substituted in the phenyl group with Metlioxycarbonvi or carboxy 1, is hydrogen, methyl or a group of the formula stands in which # 9 identifies the point of attachment with -CHCFbPhenyl,
  • R 12 is phenyl which may be substituted with metlioxycarbonyl, carboxy or a group of the formula -S (O) 20H,
  • R is phenyl which may be substituted by methoxycarbonyl or carboxyi
  • R 35 represents methyl or hydroxy, and their salts, solvates and solvates of the salts.
  • Preferred subject matter of the present invention are compounds of the formula (XXXI) as stated above, in which L 1 represents a bond,
  • R 1 is hydrogen
  • R is benzyl or lif-indol-3-ylmethyl
  • R 3 is hydrogen
  • R 4 is benzyl or 1H-indol-3-ylmethyl, or R 3 and R 4 together with the carbon atom to which they are attached form a (15,2R) -2-phenylcyclopropane-1,1-diyl group of the formula
  • R 7 is hydrogen
  • R 5 is hydrogen
  • R y is hydrogen, R 35 is methyl, and their salts, solvates and solvates of the salts.
  • L 1 is a bond
  • L 2 is linear (C 2 -C 6) -alkanediyl or a group of the formula stands, where p is a number of 2 or 3 which indicates the point of attachment to the group B,
  • R z is 4-hydroxybenzyl or 1H-indol-3-ylmethyl, or
  • # 5 denotes the point of attachment with the carbonyl group, the ring A with the -O-moiety contained therein for a mono- or bicyclic, optionally substituted heterocycle of the formula stands in which
  • # ö denotes the point of attachment with the carbonyl group
  • R 6 represents hydrogen, hydroxyl or benzyloxy
  • R J represents hydrogen
  • R A is 4-hydroxybenzyl or 1H-indol-3-ynethyl, or
  • R ? stands for hydrogen, stands for hydrogen,
  • R 9 is hydrogen, R 35 is methyl, and their salts, solvates and solvates of the salts.
  • Preferred subject matter of the present invention are compounds of the formulas (XXXa) and (XXXI) selected from the group: N- [6- (3- ⁇ [(2R) -2-amino-2-carboxyethyl] sulfanyl ⁇ -2,5- dioxopyrrolidin-1-yl) hexyl] -N-methyl-L-valyl-iV-i (3R, 4S, 5S) - 1 - ⁇ (2S) -2- [(IR, 2R) -3 - ⁇ [( ⁇ S) - ⁇ -carboxy-2- (1H-indol-3-yl) ethyl] amino ⁇ -1-methoxy-2-methyl-3-oxopropyl] pyrrolidin-1-yl ⁇ -3-methoxy-5-methyl oxoheptan-4-yl] -N-metyl-L-valinamide,
  • a further subject of the present invention are binder active compound conjugates of the general formula (I)
  • n is a number from 1 to 50
  • AK stands for a binder
  • group ⁇ -GL 1 -BL 2 - ⁇ stands for a linker
  • ⁇ denotes the linking position with the group AK
  • ⁇ denotes the linking position with the nitrogen atom
  • D represents a group of the formula
  • R 1 is hydrogen
  • R 2 is 1-hydroxyethyl, benzyl, 1-phenylethyl or 1H-indol-3-ylmethyl, or
  • # 5 denotes the point of attachment with the Carbonyi group, the ring A with the NO group contained therein for a mono- or bicyclic, optionally substituted heterocycle of the formula
  • R 6 is hydrogen, hydroxy or benzyloxy
  • R 3 is hydrogen
  • R 4 is 1-hydroxyethyl, benzyl, 1-phenylethyl or 1H-indol-3-ylmethyl, or
  • R 7 is hydrogen, methyl, ethyl, w-propyl, terr. Butyl, benzyl or adamantylmethyl,
  • R 8 is hydrogen or methyl
  • R 9 is hydrogen, methyl, ethyl, w-propyl or benzyl, or
  • R 8 and R 9 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle
  • R i0 is benzoyl
  • R ' 1 for benzyl which may be substituted in the Phenylgnippe with methoxycarbonyl or carboxy, stands for hydrogen, methyl or a group of the formula
  • R ' 2 is phenyl which may be substituted by methoxycarbonyl, carboxyi or a group of the formula -SiOjiOH,
  • R 13 is phenyl which may be substituted by methoxycarbonyl or carboxy, represents hydrogen or hydroxy
  • T 2 is phenyl, benzyl, 1H-indol-3-yl or 1H-indol-3-ylmetyl, and their salts, solvates and solvates of the salts.
  • Preferred subject of the invention are binder active ingredient conjugates of the general formula ( ⁇ ), in which n is a number from 1 to 50, AK for AK: or AK 2 is
  • # denotes the point of attachment to the sulfur atom of the binder
  • the point of attachment to the group G denotes, ##
  • the Verknüpfungssielle with the group B denotes, wherein (Ci-Cio) -alkyl having 1 to 4 Substituenlen methyl may be substituted in, and wherein two carbon atoms of the alkanediyl chain in Figure 1, 2-, 1,3- or 1,4-relative to each other, including the carbon atoms which may be located between them to a (Ca-Cej-cycloalkyl ring or a phenyl ring may be bridged, for a bond or a group of the formula
  • L 3 is a bond or (C 2 -C 4) -alkanediyl
  • L 4 represents a bond or a group of the formula
  • Q 2 is a 3- to 7-membered carbocycle or a 4- to 7-membered heterocyci
  • R 14 is hydrogen or (C 5 -C) -alkyl
  • R 15 is hydrogen or (Ci-C4) -alkyl, or
  • R ⁇ and R ' 3 together with the atoms to which they are attached form a 5- or 6-membered heterocyci
  • R 16 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 17 is hydrogen or (Ci-C 4 ) -alkyl, or
  • R 16 and R 17 together with the atoms to which they are attached form a 5- or 6-membered heterocyci
  • R 18 is hydrogen or (C 1 -C 4 ) -alkyl
  • R 19 is hydrogen or the side group of a natural ⁇ -amino acid or its homologs or isomers
  • R 20 is hydrogen or (C 1 -C 4 ) -alkyl, or

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Families Citing this family (62)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UY32560A (es) 2009-04-29 2010-11-30 Bayer Schering Pharma Ag Inmunoconjugados de antimesotelina y usos de los mismos
NZ600470A (en) * 2009-12-09 2015-02-27 Bayer Pharma AG Anti-c4.4a antibodies and uses thereof
EP2579887B1 (de) * 2010-06-10 2014-11-12 Seattle Genetics, Inc. Neue auristatin-derivate und ihre verwendung
US8987209B2 (en) 2010-09-29 2015-03-24 Seattle Genetics, Inc. N-carboxyalkyl-auristatin and the use thereof
US9029406B2 (en) 2011-03-16 2015-05-12 Seattle Genetics, Inc N-carboxyalkylauristatins and use thereof
EP2699268A2 (de) 2011-04-21 2014-02-26 Seattle Genetics, Inc. Neue binder-wirkstoff konjugate (adcs) und ihre verwendung
WO2013087716A2 (de) * 2011-12-14 2013-06-20 Bayer Pharma Aktiengesellschaft Neue binder-wirkstoff konjugate (adcs) und ihre verwendung
EP2928503B1 (en) 2012-12-10 2019-02-20 Mersana Therapeutics, Inc. Conjugates of auristatin compounds
JP6262768B2 (ja) * 2013-01-03 2018-01-17 セルトリオン， インク． 抗体−リンカー−薬物結合体、その製造方法およびそれを含む抗癌剤組成物
MX368258B (es) 2013-03-15 2019-09-25 Zymeworks Inc Compuestos citotoxicos y antimitoticos y metodos de uso de los mismos.
FR3005051A1 (fr) * 2013-04-25 2014-10-31 Pf Medicament Derives de la dolastatine 10 et d'auristatines
US9517276B2 (en) * 2013-06-04 2016-12-13 Cytomx Therapeutics, Inc. Compositions and methods for conjugating activatable antibodies
TR201909034T4 (tr) * 2013-10-25 2019-07-22 Bayer Pharma AG Yeni bir stabil formülasyon.
EP3082874A2 (en) * 2013-12-16 2016-10-26 Genentech, Inc. Peptidomimetic compounds and antibody-drug conjugates thereof
AU2014364812B2 (en) 2013-12-17 2017-05-25 Novartis Ag Cytotoxic peptides and conjugates thereof
NZ720736A (en) 2013-12-23 2020-08-28 Bayer Pharma AG Antibody drug conjugates (adcs) with kinesin spindel protein (ksp)
CN106459162A (zh) 2013-12-27 2017-02-22 酵活有限公司 Var2csa‑药物偶联物
KR102384740B1 (ko) 2013-12-27 2022-04-07 자임워크스 인코포레이티드 약물 접합체를 위한 설폰아마이드-함유 연결 시스템
PT3122757T (pt) * 2014-02-28 2023-11-03 Hangzhou Dac Biotech Co Ltd Ligantes carregados e as suas utilizações em conjugação
US9260478B2 (en) 2014-04-04 2016-02-16 Shanghui Hu Potent and efficient cytotoxic peptides and antibody-drug conjugates thereof and their synthesis
KR102413079B1 (ko) * 2014-05-28 2022-06-24 어젠시스 인코포레이티드 돌라프로인-돌라이소류인 펩타이드의 유도체
JP6681346B2 (ja) 2014-06-13 2020-04-15 ノバルティス アーゲー オーリスタチン誘導体およびその抱合体
HUE057768T2 (hu) 2014-09-17 2022-06-28 Zymeworks Inc Citotoxikus és antimitotikus vegyületek és azok alkalmazásának módszerei
CN105820248A (zh) * 2015-01-07 2016-08-03 上海张江生物技术有限公司 一种新型抗egfr单克隆抗体的制备方法及应用
US20180177890A1 (en) * 2015-02-15 2018-06-28 Jiangsu Hengrui Medicine Co., Ltd. Ligand-cytotoxic drug conjugate, preparation method thereof, and use thereof
EP3271329B1 (en) * 2015-03-19 2021-08-18 Hangzhou Dac Biotech Co., Ltd Novel hydrophilic linkers and ligand-drug conjugates thereof
AU2016249839B2 (en) * 2015-04-17 2021-09-09 Ventana Medical Systems, Inc. Antibodies, compositions, and immunohistochemistry methods for detecting C4.4a
EP3286172B1 (en) 2015-04-23 2019-06-12 Constellation Pharmaceuticals, Inc. Lsd1 inhibitors and uses thereof
CN116726190A (zh) * 2015-06-20 2023-09-12 杭州多禧生物科技有限公司 澳瑞他汀类似物及其与细胞结合分子的共轭偶联物
CN108025084A (zh) 2015-06-22 2018-05-11 拜耳医药股份有限公司 具有酶可裂解基团的抗体药物缀合物（adc）和抗体前药缀合物（apdc）
JP6928354B2 (ja) * 2015-07-24 2021-09-01 ペティット，ジョージ，ロバート クインスタチン化合物
US10722593B2 (en) 2015-10-02 2020-07-28 Sirenas Llc Anti-cancer compounds and conjugates thereof
WO2017060322A2 (en) 2015-10-10 2017-04-13 Bayer Pharma Aktiengesellschaft Ptefb-inhibitor-adc
EP3421463A4 (en) * 2016-02-26 2019-10-23 Jiangsu Hengrui Medicine Co., Ltd. NEW TOXIN AND METHOD FOR PRODUCING AN INTERMEDIATE PRODUCT THEREOF
WO2017161206A1 (en) 2016-03-16 2017-09-21 Halozyme, Inc. Conjugates containing conditionally active antibodies or antigen-binding fragments thereof, and methods of use
WO2017162663A1 (de) 2016-03-24 2017-09-28 Bayer Pharma Aktiengesellschaft Prodrugs von cytotoxischen wirkstoffen mit enzymatisch spaltbaren gruppen
JP7022707B2 (ja) 2016-06-15 2022-02-18 バイエル・ファルマ・アクティエンゲゼルシャフト Ｋｓｐ阻害剤および抗ｃｄ１２３抗体を含む特異的抗体－薬物－コンジュゲート（ａｄｃ）
WO2018006785A1 (zh) * 2016-07-05 2018-01-11 江苏恒瑞医药股份有限公司 Egfr抗体-药物偶联物及其在医药上的应用
US10517958B2 (en) 2016-10-04 2019-12-31 Zymeworks Inc. Compositions and methods for the treatment of platinum-drug resistant cancer
RS64889B1 (sr) 2016-10-26 2023-12-29 Constellation Pharmaceuticals Inc Inhibitori lsd1 i njihova medicinska upotreba
WO2018114798A1 (de) 2016-12-21 2018-06-28 Bayer Aktiengesellschaft Prodrugs von cytotoxischen wirkstoffen mit enzymatisch spaltbaren gruppen
CN110072556B (zh) 2016-12-21 2023-05-02 拜耳制药股份公司 具有ksp抑制剂的特异性抗体药物缀合物(adc)
KR102583006B1 (ko) 2016-12-21 2023-09-27 바이엘 파마 악티엔게젤샤프트 효소적으로 절단가능한 기를 갖는 항체 약물 접합체 (adc)
IL271965B2 (en) * 2017-07-12 2023-03-01 Nouscom Ag Preparations containing a neoantigenic vaccine for the treatment of cancer
US10646585B2 (en) 2017-09-15 2020-05-12 Hangzhou Dac Biotech Co., Ltd. Hydrophilic linkers and ligand-drug conjugates thereof
CN107998453B (zh) * 2017-12-12 2020-09-25 中山大学附属第一医院 一种表面改性的脱细胞基质及其改性方法
GB201721265D0 (en) * 2017-12-19 2018-01-31 Bicyclerd Ltd Bicyclic peptide ligands specific for EphA2
EP3746079A1 (en) 2018-01-31 2020-12-09 Bayer Aktiengesellschaft Antibody drug conjugates (adcs) with nampt inhibitors
MA52135A (fr) 2018-03-23 2021-01-27 Seagen Inc Utilisation de conjugués anticorps-médicament comprenant des agents de rupture de tubuline pour traiter une tumeur solide
WO2021013693A1 (en) 2019-07-23 2021-01-28 Bayer Pharma Aktiengesellschaft Antibody drug conjugates (adcs) with nampt inhibitors
WO2021142043A1 (en) * 2020-01-06 2021-07-15 Cytomx Therapeutics, Inc. Anti-slc34a2 antibodies, antibody drug conjugates, and methods of use thereof
US20240024499A1 (en) * 2020-11-19 2024-01-25 Ardeagen Corporation Gpc3 binding agents, conjugates thereof and methods of using the same
CA3199562A1 (en) * 2020-11-20 2022-05-27 Bliss Biopharmaceutical (Hangzhou) Co., Ltd. Modified egfr antibody with reduced affinity, drug conjugate, and use thereof
EP4319746A1 (en) * 2021-04-06 2024-02-14 Hemoshear Therapeutics, Inc. Methods of treating methylmalonic acidemia and propionic acidemia
JPWO2023033129A1 (ko) 2021-09-03 2023-03-09
CN115957338A (zh) * 2021-10-12 2023-04-14 成都科岭源医药技术有限公司 一种高稳定性的靶向接头-药物偶联物
WO2023092099A1 (en) 2021-11-19 2023-05-25 Ardeagen Corporation Gpc3 binding agents, conjugates thereof and methods of using the same
CN114149343B (zh) * 2021-12-06 2023-10-20 中节能万润股份有限公司 一种高纯度1,4-二氰基-2-丁烯的制备方法
WO2023240135A2 (en) 2022-06-07 2023-12-14 Actinium Pharmaceuticals, Inc. Bifunctional chelators and conjugates
WO2023237050A1 (en) * 2022-06-09 2023-12-14 Beigene, Ltd. Antibody drug conjugates
WO2024023735A1 (en) * 2022-07-27 2024-02-01 Mediboston Limited Auristatin derivatives and conjugates thereof
CN116239513B (zh) * 2023-05-05 2023-08-18 天津凯莱英制药有限公司 Mmae关键中间体的制备方法、mmae的制备方法和抗体偶联药物

Family Cites Families (107)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1981003688A1 (en) 1980-06-13 1981-12-24 Crosby Valve & Eng Co Ltd Fluid pressure relief system actuator
FR2499737B1 (fr) 1981-02-12 1985-07-05 Laudren Cie Sa Ets M Circuit d'alarme pour systemes de surveillance de postes telephoniques publics a prepaiement
US4474893A (en) 1981-07-01 1984-10-02 The University of Texas System Cancer Center Recombinant monoclonal antibodies
US4714681A (en) 1981-07-01 1987-12-22 The Board Of Reagents, The University Of Texas System Cancer Center Quadroma cells and trioma cells and methods for the production of same
DE3265843D1 (en) 1981-07-30 1985-10-03 Shell Int Research Process for the preparation of carbonate esters
DE3223868A1 (de) 1982-06-25 1983-12-29 Friedrich 8541 Röttenbach Schweinfurter Turbinenpumpe
GR81257B (ko) 1982-12-04 1984-12-11 Lilly Industries Ltd
GB8308235D0 (en) 1983-03-25 1983-05-05 Celltech Ltd Polypeptides
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
GB2163883B (en) 1984-08-29 1989-02-01 British Aerospace Data processing arrangement
FR2576708B1 (fr) 1985-01-25 1987-04-30 Novatome Generateur de vapeur dont le fluide caloporteur est du metal liquide et dont la detection des fuites est effectuee par prelevement de ce metal liquide
US4606662A (en) 1985-01-31 1986-08-19 International Business Machines Corporation Single stepping motor ribbon and correction feed and lift system
US4640839A (en) 1985-07-01 1987-02-03 Nestec S.A. Agglomeration process
DE8808645U1 (ko) 1988-07-06 1988-08-25 Hofer, Daniel, 7730 Villingen-Schwenningen, De
US4925648A (en) 1988-07-29 1990-05-15 Immunomedics, Inc. Detection and treatment of infectious and inflammatory lesions
US5601819A (en) 1988-08-11 1997-02-11 The General Hospital Corporation Bispecific antibodies for selective immune regulation and for selective immune cell binding
ES2096590T3 (es) 1989-06-29 1997-03-16 Medarex Inc Reactivos biespecificos para la terapia del sida.
EP0595798B1 (en) 1989-10-20 1999-03-03 Medarex, Inc. Bispecific heteroantibodies with dual effector functions
US5270163A (en) 1990-06-11 1993-12-14 University Research Corporation Methods for identifying nucleic acid ligands
WO1992005793A1 (en) 1990-10-05 1992-04-16 Medarex, Inc. Targeted immunostimulation with bispecific reagents
EP0557300B1 (en) 1990-10-29 1997-11-19 Chiron Corporation Bispecific antibodies, method of production, and uses thereof
CA2082160C (en) 1991-03-06 2003-05-06 Mary M. Bendig Humanised and chimeric monoclonal antibodies
AU665758B2 (en) 1991-04-26 1996-01-18 Surface Active Limited Novel antibodies, and methods for their use
PT627940E (pt) 1992-03-05 2003-07-31 Univ Texas Utilizacao de imunoconjugados para o diagnostico e/ou terapia de tumores vascularizados
DK0719859T3 (da) 1994-12-20 2003-10-20 Merck Patent Gmbh Anti-alfa V-integrin monoklonalt antistof
ES2176484T3 (es) 1995-08-18 2002-12-01 Morphosys Ag Bancos de proteinas/(poli)peptidos.
US6150508A (en) 1996-03-25 2000-11-21 Northwest Biotherapeutics, Inc. Monoclonal antibodies specific for the extracellular domain of prostate-specific membrane antigen
EP0914155B1 (en) 1996-03-25 2006-02-22 Medarex, Inc. Monoclonal antibodies specific for the extracellular domain of prostate specific membrane antigen
EP1098666B1 (en) * 1998-07-17 2013-01-16 The United States of America, represented by the Secretary, Department of Health and Human Services Water-soluble drugs and methods for their production
IL146480A0 (en) 1999-05-14 2002-07-25 Imclone Systems Inc Treatment of refractory human tumors with epidermal growth factor receptor antagonists
WO2000069472A2 (en) 1999-05-14 2000-11-23 Boehringer Ingelheim Pharmaceuticals, Inc. Enzyme-activated anti-tumor prodrug compounds
ES2277846T3 (es) 1999-07-29 2007-08-01 Medarex, Inc. Anticuerpos monoclonales humanos para antigeno prostatico especifico.
US6323315B1 (en) 1999-09-10 2001-11-27 Basf Aktiengesellschaft Dolastatin peptides
WO2001023553A2 (en) 1999-09-29 2001-04-05 Deutsches Krebsforschungszentrum Stiftung des öffentlichen Rechts Metastasis-associated antigen c4.4a
MXPA02008178A (es) 2000-02-25 2004-04-05 Us Gov Health & Human Serv Scfvs anti-egfrviii con citotoxicidad y rendimiento mejorados, inmunotoxinas en base a los mismos y metodos para su uso.
ES2259030T3 (es) 2000-05-19 2006-09-16 Scancell Limited Anticuerpos humanizados frente al receptor del factor de crecimiento epidermico.
US7288390B2 (en) 2000-08-07 2007-10-30 Centocor, Inc. Anti-dual integrin antibodies, compositions, methods and uses
AUPR395801A0 (en) 2001-03-26 2001-04-26 Austin Research Institute, The Antibodies against cancer
CA2715570A1 (en) 2001-04-26 2002-11-07 Biogen Idec Ma Inc. Cripto blocking antibodies and uses thereof
AU2002334799B2 (en) 2001-04-26 2009-05-07 Biogen Ma Inc. Cripto-specific antibodies
US6884869B2 (en) 2001-04-30 2005-04-26 Seattle Genetics, Inc. Pentapeptide compounds and uses related thereto
US7589180B2 (en) 2001-05-11 2009-09-15 Abbott Laboratories Inc. Specific binding proteins and uses thereof
US7595378B2 (en) 2001-06-13 2009-09-29 Genmab A/S Human monoclonal antibodies to epidermal growth factor receptor (EGFR)
KR20090125840A (ko) 2001-06-13 2009-12-07 젠맵 에이/에스 표피 성장 인자 수용체 (ｅｇｆｒ)에 대한 인간 모노클로날 항체
US7091186B2 (en) 2001-09-24 2006-08-15 Seattle Genetics, Inc. p-Amidobenzylethers in drug delivery agents
WO2003026577A2 (en) 2001-09-24 2003-04-03 Seattle Genetics, Inc. P-amidobenzylethers in drug delivery agents
BRPI0308585B8 (pt) 2002-03-13 2021-05-25 Biogen Idec Inc anticorpo isolado ou fragmento de ligação a antígeno do mesmo que se liga à alfavbeta6, composição, método de detecção in vitro de alfavbeta6 e construção de dna
WO2005056606A2 (en) 2003-12-03 2005-06-23 Xencor, Inc Optimized antibodies that target the epidermal growth factor receptor
AU2003277087B2 (en) 2002-06-14 2008-07-31 Immunomedics, Inc. Humanized monoclonal antiboby hPAM4
PT1545613E (pt) 2002-07-31 2011-09-27 Seattle Genetics Inc Conjugados de auristatina e sua utilização para tratamento do cancro, de uma doença autoimune ou de uma doença infecciosa
AU2004229543A1 (en) 2003-04-11 2004-10-28 Medimmune, Llc EphA2 and non-neoplastic hyperproliferative cell disorders
CN104059147A (zh) 2003-06-27 2014-09-24 艾默根佛蒙特有限公司 针对表皮生长因子受体的缺失突变体的抗体及其使用
CN103145844B (zh) 2003-07-21 2016-08-03 伊缪诺金公司 Ca6抗原特异性细胞毒性偶联物及其应用方法
SG10201701737XA (en) * 2003-11-06 2017-04-27 Seattle Genetics Inc Monomethylvaline compounds capable of conjugation to ligands
US7767792B2 (en) 2004-02-20 2010-08-03 Ludwig Institute For Cancer Research Ltd. Antibodies to EGF receptor epitope peptides
PL1735348T3 (pl) 2004-03-19 2012-11-30 Imclone Llc Ludzkie przeciwciało przeciwko receptorowi naskórkowego czynnika wzrostu
JP4861308B2 (ja) * 2004-04-07 2012-01-25 ジェネンテック， インコーポレイテッド 抗体結合体の質量分析
MX2007003907A (es) * 2004-10-05 2007-05-21 Genentech Inc Agentes terapeuticos con toxicidad reducida.
EP1817336B1 (en) 2004-11-12 2019-01-09 Seattle Genetics, Inc. Auristatins having an aminobenzoic acid unit at the n terminus
EP2305716B1 (en) * 2004-11-30 2014-10-22 Celldex Therapeutics, Inc. Antibodies directed to gpnmb and uses thereof
PT1819359E (pt) 2004-12-09 2015-05-28 Janssen Biotech Inc Imunoconjugados anti-integrina, métodos para a sua produção e sua utilização
DK1841793T3 (da) 2005-01-07 2010-07-19 Diadexus Inc Ovr110-antistofsammensætninger og fremgangsmåder til anvendelse deraf
RU2492186C2 (ru) 2005-02-18 2013-09-10 Медарекс Ллс Выделенное анти-cd30 антитело (варианты), хозяйская клетка, способ получения химерного или гуманизированного варианта анти-cd30 антител (варианты), способ ингибирования роста клеток cd30+ и способ ингибирования роста опухолевых клеток, экспрессирующих cd30
WO2007059082A1 (en) * 2005-11-10 2007-05-24 Curagen Corporation Method of treating ovarian and renal cancer using antibodies against t cell immunoglobulin domain and mucin domain 1 (tim-1) antigen
JP5171621B2 (ja) 2005-07-07 2013-03-27 シアトル ジェネティックス， インコーポレイテッド フェニルアラニン側鎖修飾をｃ末端に有するモノメチルバリン化合物
WO2007008848A2 (en) 2005-07-07 2007-01-18 Seattle Genetics, Inc. Monomethylvaline compounds having phenylalanine carboxy modifications at the c-terminus
IL305084A (en) 2005-08-24 2023-10-01 Immunogen Inc A process for preparing purified drug compounds
US20090304721A1 (en) * 2005-09-07 2009-12-10 Medlmmune, Inc Toxin conjugated eph receptor antibodies
ES2527961T3 (es) 2005-09-26 2015-02-02 Medarex, L.L.C. Anticuerpos monoclonales humanos para CD70
DOP2006000277A (es) 2005-12-12 2007-08-31 Bayer Pharmaceuticals Corp Anticuerpos anti mn y métodos para su utilización
CN103030696B (zh) * 2006-05-30 2016-09-28 健泰科生物技术公司 抗体和免疫偶联物及其用途
WO2008004834A1 (en) 2006-07-06 2008-01-10 Isu Abxis Co., Ltd Humanized monoclonal antibody highly binding to epidermal growth factor receptor, egf receptor
ATE551071T1 (de) 2006-09-08 2012-04-15 Medimmune Llc Humanisierte anti-cd19-antikörper und ihre verwendung für die behandlung von krebs, transplantationen und autoimmunerkrankungen
BRPI0716997B8 (pt) 2006-09-10 2021-05-25 Glycotope Gmbh proteína ou composição de moléculas de proteína, métodos para produção e uso da mesma
AU2007299843B2 (en) 2006-09-18 2012-03-08 Xencor, Inc Optimized antibodies that target HM1.24
WO2008133641A2 (en) * 2006-10-11 2008-11-06 Curagen Corporation Antibodies directed to gpnmb and uses thereof
EP1914242A1 (en) 2006-10-19 2008-04-23 Sanofi-Aventis Novel anti-CD38 antibodies for the treatment of cancer
ES2523915T5 (es) 2006-12-01 2022-05-26 Seagen Inc Agentes de unión a la diana variantes y usos de los mismos
US8652466B2 (en) 2006-12-08 2014-02-18 Macrogenics, Inc. Methods for the treatment of disease using immunoglobulins having Fc regions with altered affinities for FcγRactivating and FcγRinhibiting
WO2008092117A2 (en) 2007-01-25 2008-07-31 Xencor, Inc. Immunoglobulins with modifications in the fcr binding region
EP2188311B1 (en) 2007-08-14 2016-10-05 Ludwig Institute for Cancer Research Ltd. Monoclonal antibody 175 targeting the egf receptor and derivatives and uses thereof
US8865875B2 (en) 2007-08-22 2014-10-21 Medarex, L.L.C. Site-specific attachment of drugs or other agents to engineered antibodies with C-terminal extensions
US8039597B2 (en) 2007-09-07 2011-10-18 Agensys, Inc. Antibodies and related molecules that bind to 24P4C12 proteins
WO2009033094A2 (en) 2007-09-07 2009-03-12 Agensys, Inc. Antibodies and related molecules that bind to 24p4c12 proteins
PL2195017T3 (pl) * 2007-10-01 2015-03-31 Bristol Myers Squibb Co Ludzkie antyciała, które wiążą mezotelinę i ich zastosowania
US9023351B2 (en) * 2007-11-26 2015-05-05 Bayer Intellectual Property Gmbh Anti-mesothelin antibodies and uses thereof
PL2801584T3 (pl) 2007-12-26 2019-12-31 Biotest Ag Środki mające za cel CD138 i ich zastosowania
CN101965366B (zh) 2007-12-26 2016-04-27 生物测试股份公司 靶向cd138的免疫缀合物及其应用
WO2009099728A1 (en) * 2008-01-31 2009-08-13 Genentech, Inc. Anti-cd79b antibodies and immunoconjugates and methods of use
EP2285584A4 (en) 2008-02-25 2012-01-25 Prittie Family Trust 89 IMAGE PLATE STRUCTURE FOR HIGH PRESSURE WITH AREAS OF DIFFERENT BEAM THICKNESS BETWEEN THE PICTURES
EP2260111B2 (en) * 2008-03-14 2022-03-23 Genentech, Inc. Genetic variations associated with drug resistance
US8609105B2 (en) 2008-03-18 2013-12-17 Seattle Genetics, Inc. Auristatin drug linker conjugates
BRPI0906309A2 (pt) 2008-04-02 2020-05-26 Macrogenics, Inc Imunoglobulina, anticorpo, uso do anticorpo e composição farmacêutica
EP2277044B1 (en) * 2008-05-13 2015-06-17 Genentech, Inc. Analysis of antibody drug conjugates by bead-based affinity capture and mass spectrometry
AU2009287163B2 (en) 2008-08-29 2014-11-13 Les Laboratoires Servier Recombinant anti-Epidermal Growth Factor Receptor antibody compositions
US20100247484A1 (en) 2009-03-31 2010-09-30 Heinrich Barchet Combination therapy of an afucosylated antibody and one or more of the cytokines gm csf, m csf and/or il3
AU2010230346A1 (en) 2009-03-31 2011-07-28 Roche Glycart Ag Treatment of cancer with a humanized anti-EGFR IgG1antibody and irinotecan
ES2661238T3 (es) 2009-06-19 2018-03-28 Merck Patent Gmbh Biomarcadores y métodos para determinar la eficacia de anticuerpos anti-EGFR en la terapia del cáncer
CA2776385C (en) 2009-10-07 2019-04-09 Macrogenics, Inc. Fc region-containing polypeptides that exhibit improved effector function due to alterations of the extent of fucosylation, and methods for their use
NZ600470A (en) * 2009-12-09 2015-02-27 Bayer Pharma AG Anti-c4.4a antibodies and uses thereof
EP2579887B1 (de) * 2010-06-10 2014-11-12 Seattle Genetics, Inc. Neue auristatin-derivate und ihre verwendung
US8987209B2 (en) 2010-09-29 2015-03-24 Seattle Genetics, Inc. N-carboxyalkyl-auristatin and the use thereof
AU2011349443B2 (en) * 2010-12-20 2015-12-24 Genentech, Inc. Anti-mesothelin antibodies and immunoconjugates
US9302799B2 (en) * 2011-02-17 2016-04-05 Sabic Global Technologies B.V. Method for bulk transporting 2,6-xylenol susceptible to oxidative discoloration
US9029406B2 (en) 2011-03-16 2015-05-12 Seattle Genetics, Inc N-carboxyalkylauristatins and use thereof
EP2699268A2 (de) 2011-04-21 2014-02-26 Seattle Genetics, Inc. Neue binder-wirkstoff konjugate (adcs) und ihre verwendung
WO2013087716A2 (de) 2011-12-14 2013-06-20 Bayer Pharma Aktiengesellschaft Neue binder-wirkstoff konjugate (adcs) und ihre verwendung

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

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