EP1524979A2 - Nouveaux conjugues d'effecteurs, procedes permettant de les produire et utilisation pharmaceutique de ceux-ci - Google Patents

Nouveaux conjugues d'effecteurs, procedes permettant de les produire et utilisation pharmaceutique de ceux-ci

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Publication number
EP1524979A2
EP1524979A2 EP03743752A EP03743752A EP1524979A2 EP 1524979 A2 EP1524979 A2 EP 1524979A2 EP 03743752 A EP03743752 A EP 03743752A EP 03743752 A EP03743752 A EP 03743752A EP 1524979 A2 EP1524979 A2 EP 1524979A2
Authority
EP
European Patent Office
Prior art keywords
dione
dihydroxy
tetramethyl
methyl
oxacyclohexadec
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Withdrawn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
EP03743752A
Other languages
German (de)
English (en)
Inventor
Markus Berger
Gerhard Siemeister
Ulrich Klar
Jörg WILLUDA
Andreas Menrad
Klaus Bosslet
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.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE10234975A external-priority patent/DE10234975A1/de
Priority claimed from DE10305098A external-priority patent/DE10305098A1/de
Application filed by Schering AG filed Critical Schering AG
Publication of EP1524979A2 publication Critical patent/EP1524979A2/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
    • A61K47/6809—Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • a precondition for such an approach in which a highly active (toxic) active agent (effector) is coupled to a high-molecular, tumor-specific recognition unit, such as, for example, to an antibody, is a substantial inactivity of the conjugate, whose minimum components are represented by a recognition unit and an effector, until it has reached the target site (tumor). Arriving at the target site, the conjugate binds to the cell surface and the active ingredient, optionally after the preceding internalization of the entire complex, can be released.
  • a highly active (toxic) active agent (effector) is coupled to a high-molecular, tumor-specific recognition unit, such as, for example, to an antibody
  • a substantial inactivity of the conjugate whose minimum components are represented by a recognition unit and an effector, until it has reached the target site (tumor). Arriving at the target site, the conjugate binds to the cell surface and the active ingredient, optionally after the preceding internalization of the entire complex, can be released.
  • the successful therapy of solid tumors can be limited, however, by an inadequate penetration of the antibody into the tumor as well as the heterogeneous dispersion of the corresponding tumor-associated antigens in the tumor tissue.
  • These limitations could be avoided in that the tumor- vascular system is attacked in a specific way.
  • the growth of tumors below a volume of about 2 mm depends on a neoangiogenesis.
  • the subsequent tumor growth is based on an intact vascular system, which ensures the supply with nutrients or the removal of waste products.
  • the selective destruction of this system should therefore result in a necrosis of the tumor.
  • the attack on the vascular system of the tumor promises a number of advantages relative to the direct attack on the tumor itself.
  • endothelial cells are easier to access, since no tumor tissue has to be penetrated.
  • the damage of an individual tumor vessel should result in a necrosis of thousands of tumor cells.
  • To damage a tumor vessel it is not necessary to kill all endothelial cells.
  • the specific attack of endothelial cells in or close to the tumors minimizes systemic side effects.
  • Endothelial cells are genetically very stable, so that the probability of a development of resistance against the tumor therapeutic agent is low.
  • a possibility has now been found to link the chemically very sensitive, highly-functionalized class of active agents of epothilones and analogs thereof to a high-molecular recognition unit via different linkers in different positions of the active agent.
  • the object of this invention is thus, ter alia,
  • R.l a , Rib independently of one another, are hydrogen, CJ-CIQ alkyl, aryl, aralkyl, or together a -(CH2) m group, in which m is 2 to 5,
  • R2a, R2b 5 independently of one another, are hydrogen, C ⁇ -Cio alkyl, aryl, aralkyl, or together a -(CH2) n group, in which n is 2 to 5, or C2-C10 alkenyl, or C2-C10 alkynyl
  • R3 is hydrogen, C ⁇ -C ⁇ Q alkyl, aryl or aralkyl
  • R4a R4b s independently of one another, are hydrogen, CJ-CJO alkyl, aryl, aralkyl, or together a -(CH2)p group, in which p is 2 to 5,
  • R 5 is hydrogen, C 1 -C 10 alkyl, aryl, aralkyl, CO2H,
  • Hal is a halogen atom
  • R6, R ⁇ in each case are hydrogen, or together an additional bond, or together an oxygen atom, or together an NH group, or together an N-alkyl group, or together a CH2 group, and G is an oxygen atom or CH2,
  • L,3 is hydrogen, or, if a radical in W contains a hydroxyl group, forms a group O-L,4 with the latter, or, if a radical in W contains an amino group, forms a group NR25-L4 with the latter, R25 i s hydrogen or C 1 -C ⁇ Q alkyl, X is an oxygen atom, or two OR 2 ⁇ groups, or a C2-C ⁇ 0 alkylenedioxy group that may be straight-chain or branched, or H/OR9, or a CRIORI 1 group, R 8 is hydrogen, C ⁇ -Ci 0 alkyl, aryl, aralkyl, halogen or CN, and R9 is hydrogen or a protective group PG- ⁇ ,
  • R i O, R11 m eacn case independently of one another, are hydrogen, C1-C20 alkyl, aryl, aralkyl, or together with a methylene carbon atom form a 5- to 7- membered carbocyclic ring, Z can represent oxygen or H/OR 2 ,
  • R!2 can represent hydrogen or a protective group PG ⁇
  • R20 can represent C1-C20 alkyl
  • R 2 1 can represent a hydrogen atom or C ⁇ -C ⁇ Q alkyl
  • T can represent oxygen or sulfur
  • V can represent a bond, aryl, a group
  • s can represent 0 to 4,
  • R 22 can represent hydrogen, C -C ⁇ Q alkyl, aryl or aralkyl
  • R 23 can represent hydrogen or C ⁇ -C ⁇ Q alkyl
  • R 24a , R 24 ⁇ , and R 24c independently of one another, can represent hydrogen or
  • Ci-Cio alkyl, q can represent 0 to 15,
  • T can represent oxygen or sulfur
  • W 1 , W 2 are the same or different and can represent oxygen or ⁇ R 2 a , o can represent 0 to 5,
  • R 22 can represent hydrogen, Ci-C 10 alkyl, aryl or aralkyl,
  • R 23 can represent hydrogen, or C 1 -C10 alkyl
  • R 24a can represent hydrogen or C ⁇ o alkyl
  • R 27 can represent halogen, C ⁇ , ⁇ O 2 , CO 2 R 28 , or OR 28 ,
  • R 28 can represent hydrogen, C J -CK J alkyl, aryl or aralkyl,
  • q can represent 0 to 5
  • u can represent oxygen, CHR , 22 CHR ) 2 -N ⁇ rR>23
  • r can represent 0 to 20
  • FG 1 can represent -C K ) alkyl-S 3 , as a single isomer or a mixture of different isomers and/or as a pharmaceutically acceptable salt thereof.
  • the invention describes the production of effector recognition unit conjugates of general formula (I), wherein the substituents therein have the above- mentioned meanings, but at least one group FG 1 is replaced by a group FG a or FG , wherein FG 2 or FG 2b can have the following meanings:
  • FG 2b -CONH- and wherein a recognition unit is conjugated via a sulfur atom with the group FG 2a , wherein the indicated sulfur atom is a component of the recognition unit, or via an amide function of group FG 2b , wherein the indicated nitrogen atom is a component of the recognition unit; wherein the recognition unit can be, for example, a peptide, a soluble receptor, a cytokine, a lymphokine, an aptamer, a aptmer, a aptmer, a aptmer, a aptmer, a aptmer, a aptmer, a recombinant protein, a framework structure, a monoclonal antibody or a fragment of a monoclonal antibody.
  • the above-mentioned effector recognition unit conjugates can comprise one or more recognition units; in this case, the recognition units that belong to a conjugate can be identical or different. It is preferred that the recognition units of a conjugate be identical.
  • effector recognition unit conjugates according to the invention can be used in the form of their ⁇ -, ⁇ - or ⁇ -cyclodextrin-clathrates or in the form of liposomal or pegylated compositions.
  • the conjugates according to the invention are preferably used for the treatment of diseases that are associated with proliferative processes.
  • diseases that are associated with proliferative processes.
  • the therapy of different tumors the therapy of inflammatory and/or neurodegenerative diseases, such as multiple sclerosis or Alzheimer's disease, the therapy of angiogenesis- associated diseases such as the growth of solid tumors, rheumatoid arthritis or diseases of the ocular fundus, can be mentioned.
  • epothilones their precursors and derivatives of general formula I is carried out according to the methods that are known to one skilled in the art, as they are described in, for example, DE 19907588, WO 98/25929, WO 99/58534, WO 99/2514, WO 99/67252, WO 99/67253, WO 99/7692, EP 99/4915, WO 00/485, WO 00/1333, WO 00/66589, WO 00/49019, WO 00/49020, WO 00/49021, WO 00/71521, WO 00/37473, WO 00/57874, WO 01/92255, WO 01/81342, WO 01/73103, WO 01/64650, WO 01/70716, US 6204388, US 6387927, US 6380394, US 02/52028, US 02/58286, US 02/62030, WO 02/32844, WO 02/30356, WO
  • straight-chain or branched-chain alkyl groups with 1-20 carbon atoms can be considered, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, and decyl.
  • Alkyl groups Rl , Rib R 2a R 2 b R 3 , R 4a , R4b R 5 5 R 8 ⁇ R 10 3 R l 1, R 20 ? R 21 ? R 22 , R 23 , R 24 R 24b , R24c R 25 a ⁇ R 26 can also be perfluorinated or substituted by 1-5 halogen atoms, hydroxy groups, C ⁇ -C-i-alkoxy groups or Cg-C ⁇ -aryl groups (which can be substituted by 1-3 halogen atoms).
  • R 2 ⁇ and N, substituted and unsubstituted carbocyclic or heterocyclic radicals with one or more heteroatoms, such as phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl, benzothiazolyl or benzoxazolyl, which can be substituted in one or more places by halogen, OH, O-alkyl, CO 2 H, CO 2 -alkyl, - ⁇ H 2 , -NO 2 , -N 3 , -CN, C 1 -C 20 -alkyl, C 1 -C 20 -acyl or C 1 -C 20 - acyloxy groups, are suitable.
  • heteroatoms such as phenyl, naphthyl, furyl, thienyl, pyrid
  • heteroatoms can be oxidized provided that this does not cause the aromatic character to be lost, such as, for example, the oxidation of a pyridyl to a pyridyl-N-oxide.
  • bicyclic and tricyclic aryl radicals W substituted and unsubstituted, carbocyclic or heterocyclic radicals with one or more heteroatoms such as naphthyl, anthryl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolyl, isoquinolyl, benzoxazinyl, benzofuranyl, indolyl, indazolyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thienopyridinyl, pyridopyridinyl, benzopyrazolyl, benzotriazolyl, or dihydroindolyl, which can be substituted in one or
  • the aralkyl groups in Rla, R b, R 2 R 2 b R 3, R 4a R 4b R 5, R 8 ? R 10 5 R ll s R 22 and R 2 ⁇ can contain in the ring up to 14 C atoms, preferably 6 to 10 C atoms, and in the alkyl chain 1 to 8 atoms, preferably 1 to 4 atoms.
  • an aralkyl radical for example, benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl or pyridylpropyl is suitable.
  • the rings can be substituted in one or more places by halogen, OH, O-alkyl, CO2H, CO2-alkyl, -NO2, -N3, -CN, Cl-C20 _ acyl or C ⁇ -C2 ⁇ - cylo y groups.
  • protective groups PG tris(Cj-C20 alkyl)silyl, bis(Cj-C20 alkyl)-arylsilyl, (C1-C20 alkyl)-diarylsilyl, tris(aralkyl)-silyl, C ⁇ -C2()- lkyl, C2-C20- alkenyl, C ⁇ Cy-cycloalkyl, which in addition can contain an oxygen atom in the ring, aryl, C7-C2()-aralkyl, Cj-C20-acyl, aroyl, C ⁇ -C20-alkoxycarbonyl, C1-C20- alkylsulfonyl as well as arylsulfonyl can be cited.
  • alkyl-, silyl- and acyl radicals for the protective groups PG especially the radicals that are known to one skilled in the art are considered.
  • alkoxycarbonyl radical e.g., trichloroethyloxycarbonyl (Troc) is suitable.
  • acyl radical e.g., formyl, acetyl, propionyl, isopropionyl, trichloromethylcarbonyl, pivalyl, butyryl or benzoyl, which radical can be substituted with an amino and/or hydroxy group, is suitable.
  • amino protective groups PG the radicals that are known to one skilled in the art are suitable.
  • the Alloc, Boc, Z, benzyl, f-Moc, Troc, stabase or benzostabase group can be mentioned.
  • acyl groups can contain 1 to 20 carbon atoms, formyl, acetyl, propionyl, isopropionyl and pivalyl groups being preferred.
  • the C2-C ⁇ o ⁇ a h yle ⁇ e- ⁇ , ⁇ -dioxy group that is possible for X is preferably an ethylene ketal or neopentyl ketal group.
  • Preferred compounds of general formula I are those in which A-Y represents
  • D-E represents an H2C-CH2 group
  • G represents a CH 2 group
  • Z represents an oxygen atom
  • Rl a Rib in each case represent CI-CJO ⁇ kyl or together a -(CH2)p group with p equal to 2 or 3 or 4
  • R 2a , R 2 b independently of one another, represent hydrogen, CI-CJO alkyl, C2-C10 alkenyl, or C2-C10 alkynyl
  • R 3 represents hydrogen
  • R 4a , R 4 b independently of one another, represent hydrogen or C ⁇ -CJO alkyl
  • R 5 represents hydrogen, or C1-C4 alkyl or CH2OH or CH2NH2 or CH2N(alkyl, acyl) j 2 or CH2Hal
  • X represents a CRIORI 1 group;
  • R ⁇ represents hydrogen or C1-C4 alkyl or a fluorine atom or a chlorine atom or a bromine atom;
  • RI ⁇ / I 1 represent hydrogen/2- methylthiazol-4-yl or hydrogen/2-pyridyl or hydrogen 2-methyloxazol-4-yl or hydrogen/2-aminomethylthiazol-4-y
  • linkers of general formula (IN) compounds are preferred in which o is zero to four, and q is zero to three. Especially preferred are compounds of general formula
  • binding regions derived from antibodies so-called CDRs, are suitable.
  • framework structures for use as recognition units for example, high- molecular structures that are not derived from antibodies are suitable.
  • structures of the fibronectin type 3 and of crystallins can be mentioned.
  • fragments of monoclonal antibodies for use as recognition units for example, single-chain Fv, Fab, F(ab) 2 as well as recombinant multimers can be mentioned.
  • recognition units those are considered that are suitable for, for example, the recognition and or diagnosis and/or therapy of solid tumors and malignant diseases of the hematopoietic system.
  • recognition units that are additionally preferred, those are considered that allow a selective recognition of the disease-specific vascular system, preferably of the angiogenesis.
  • Table 1 cites examples of especially preferred recognition units for treating solid tumors. TABLE 1
  • antibodies or antibody fragments such as CD19, CD20, CD40, CD22, CD25, CD5, CD52, CD10, CD2, CD7, CD33, CD38, CD40, CD72, CD4, CD21, CD5, CD37 and CD30, can also be mentioned.
  • antibodies or fragments thereof such as NCAM, CD31, ELAM, endoglin, NEGFRI/II, ⁇ v ⁇ 3 , Tiel/2, TES23 (CD44ex6), phosphatidylserine, PSMA, NEGFR/NEGF complex or ED-B-fibronectin, can be mentioned.
  • the compounds that are mentioned below are especially preferred according to the invention as effector elements:
  • the invention also relates to linkers of general formula III
  • R 26 can be C ⁇ -C ⁇ o alkyl, aryl, or aralkyl, and o, V, q, T and FGl have the meanings that are already mentioned above, as well as linkers of general formula III
  • RG 3 can be an OH group or an NHR 2 4a group or a COOH group, and o, N, q and FGl have the meanings that are already mentioned above; but with the proviso that the compound l-(4-amino-phenyl)-pyrrole-2,5-dione is not included.
  • the invention also relates to linkers of general formula (IN 1 ):
  • RG 3 is an OH group or an ⁇ HR 24a group or a COOH group, and R 24a , o, q, r, W 2 , R 27 , U and FG 1 have the meanings that are mentioned in claim 1.
  • linkers of general formulas III , III or III are preferred, wherein V represents a bond or an aryl radical, o is equal to zero, and T is an oxygen atom.
  • linkers of general formulas III 1 , III 2 or III 3 according to the invention are preferred, in which V represents a bond or an aryl radical or a group
  • the invention relates to methods to react a linker of general formula III 1 or IN 1 with a compound of general formula I, in which the condition that at least one group Ll , L 2 or L 4 represent a linker need not be met, and in which Ll and/or L 2 and/or L 4 have the meaning of a hydrogen atom, and free hydroxyl groups and/or amino groups that are not required for the reaction optionally are protected, to react a linker of general formula III 2 or IN 2 with a compound of general formula I, in which the condition that at least one group Ll , L 2 or l represent a linker need not be met, and Ll and/or L 2 and/or ⁇ have the meaning of a hydrogen atom, and free hydroxyl groups and/or amino groups that are not required for the reaction are optionally protected, or to react a linker of general formula III 3 or IN 3 with a compound of general formula I, in which the condition that at least one group Ll , L 2 or ⁇ represent a linker need not be met,
  • the invention also relates to the use of a linker of general formula III 1 , III 2 , III 3 ,
  • the invention also relates to the use of a linker of general formula III , III , III ,
  • the invention also relates to the use of a recognition unit, as described above, in a process according to the invention for the production of an effector recognition unit conjugate, as described above.
  • the invention also relates to the effector recognition unit conjugates according to the invention for use as a medicament or for the production of a medicament or a pharmaceutical composition.
  • the invention relates finally to the use of the effector recognition unit conjugates according to the invention for the production of medicaments for the treatment of diseases that are associated with proliferative processes, such as tumors, inflammatory and/or neurodegenerative diseases, multiple sclerosis, Alzheimer's disease, or for the treatment of angiogenesis-associated diseases, such as tumor growth, rheumatoid arthritis or diseases of the ocular fundus.
  • Example Lla in 150 ml of methanol is mixed at 23°C with 44 ml of a 5M sodium hydroxide solution, and it is stirred for 5 hours.
  • 4N hydrochloric acid a pH of 2 is set, and it is extracted with dichloromethane.
  • the combined organic extracts are washed with saturated sodium chloride solution and dried over sodium sulfate.
  • the residue that is obtained after filtration and removal of the solvent (13.0 g, maximum 67.3 mmol) is further reacted without purification.
  • Example Lid (S) 2-[(3-Methyltrisulfanyl-propionyl)-methyl-amino]-propanoic acid methyl ester The solution of 14 g (68.2 mmol) of the compound, prepared according to Example Lie, in 180 ml of trichloromethane is added to the solution of 21 g of 2- methyldisulfanyl-isoindole-l,3-dione in 420 ml of trichloromethane, and it is stirred for 16 hours at 23°C. It is concentrated by evaporation, dissolved in dichloromethane, and stirred for 0.5 hour. Solid is filtered off, the filtrate is concentrated by evaporation, and the residue is purified by chromatography on fine silica gel. 16.2 g (57.2 mmol, 84%) of the title compound is isolated as a colorless oil.
  • Example Lid in 20 ml of ethanol is mixed with 1 1 of phosphate puffer with a pH of
  • Example L2b 7.13 g (46.4 mmol) of N-methylglycine ethyl ester-hydrochloride is reacted analogously to Example Lla, and 6.9 g (27.9 mmol, 60%) of the title compound is isolated as a colorless oil.
  • Example L2b 7.13 g (46.4 mmol) of N-methylglycine ethyl ester-hydrochloride is reacted analogously to Example Lla, and 6.9 g (27.9 mmol, 60%) of the title compound is isolated as a colorless oil.
  • Example L2b 7.13 g (46.4 mmol) of N-methylglycine ethyl ester-hydrochloride is reacted analogously to Example Lla, and 6.9 g (27.9 mmol, 60%) of the title compound is isolated as a colorless oil.
  • Example L2b 7.13 g (46.4 mmol) of N-methylglycine ethyl ester-hydrochlor
  • Example L2a 7.6 g (30.7 mmol) of the compound that is prepared according to Example L2a is reacted analogously to Example Lib, and 4.92 g (27.8 mmol, 90%) of the title compound is isolated as a colorless oil.
  • Example L2b 4.92 g (27.8 mmol) of the compound that is prepared according to Example L2b is reacted analogously to Example Lie, and 5.01 g (26.2 mmol, 94%) of the title compound is isolated as a colorless oil.
  • Example L2c 2.00 g (10.5 mmol) of the compound that is prepared according to Example L2c is reacted analogously to Example Lid, and 2.33 g (8.65 mmol, 82%) of the title compound is isolated as a colorless oil.
  • Example L3c (S) 2- [(3 -Mercapto-propionyl)-methyl-amino] -3 -phenyl-propanoic acid methyl ester 0.74 g (2.77 mmol) of the compound that is prepared according to Example L3b is reacted analogously to Example Lie, and 0.77 g (2.74 mmol, 99%) of the title compound is isolated as a colorless oil.
  • Example L3d 0.72 g (2.00 mmol) of the compound that is prepared according to Example L3d is reacted analogously to Example Ll , and 0.49 g (1.42 mmol, 71%) of the title compound is isolated as a colorless oil.
  • Example L5 10.0 g (47.3 mmol) of the compound that is prepared according to Example L5 is reacted analogously to Example L4a, and 3.19 g (15.3 mmol, 32%) of the title compound is isolated as a colorless oil.
  • Example L7 l-(4-Amino-phenyl)-pyrrole-2,5-dione
  • the solution of 21.6 g (200 mmol) of 1 ,4-phenylenediamine in 200 ml of tetrahydrofuran is mixed over 1.5 hours with the solution of 19.6 g of maleic acid anhydride, and it is stirred for 22 hours at 23°C. It is filtered, rewashed with tetrahydrofuran, and the filtrate is dried. 37.1 g (197 mmol, 98%) of the title compound is isolated as a crystalline solid.
  • iH-NMR (d6-DMSO): ⁇ 6.28 (IH), 6.48 (IH), 6.53 (2H), 7.30 (2H), 7.50-
  • Example L4 in 250 ml of dichloromethane, is added dropwise within 15 minutes. It is stirred for one more hour at 23 °C, filtered, the filtrate is concentrated by evaporation and purified by chromatography on fine silica gel. 1.73 g (5.2 mmol, 18%) of the title compound is isolated.
  • 1H-NMR (CDCI3): ⁇ 2.07 (3H), 2.67 (2H), 3.67 (2H), 4.79 (2H), 6.72 (2H),
  • Example L9 Analogously to Example L9, 5.0 g (29.6 mmol) of 4-hydroxymethyl-2-nitro- phenol is reacted with 6.34 g of the compound that is prepared according to Example
  • Example L9 Analogously to Example L9, 5.0 g (29.6 mmol) of 4-hydroxymethyl-2-nitro- phenol is reacted with 8.44 g of the compound that is prepared according to Example
  • Example L12 4-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-butanoic acid 4-hydroxymethyl-phenyl ester 5.5 g (23,1 mmol) 4-tert-Butyldimethylsilanyloxymethyl-phenol, 20 mg N,N- Dimethyl-4-aminopyridine und 4.23 g (23,1 mmol) of the compound prepared according to Example L4 are dissolved in 92 ml of dichloromethane and cooled to 0°C. 4.77 g (23.1 mmol) N,N'-Dicyclohexylcarbodiimide in 24 ml dichloromethane are added dropwise to the cooled solution over a period of 15 min.
  • Example L13 6-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-hexanoic acid 4-hydroxymethyl-phenyl ester
  • 4.02 g (13.8 mmol) 4-tert- butyldimethylsilanyloxymethyl- phenol are reacted with 3.56 g (13.8 mmol) of the compound prepared according to Example L5.
  • purification and analogous treatment with p-toluenesulfonic acid 3,19 g (10.1 mmol, 60%) of the title compound are isolated.
  • Example L14 1 l-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic acid 4-hydroxymethyl-phenyl ester
  • Example L12 Analogously to Example L12, 5.41 g (22.7 mmol) 4-tert- butyldimethylsilanyloxymethyl- phenol are reacted with 6.39 g (22.7 mmol) of the compound prepared according to Example L6. After working-up, purification and analogous treatment with p-toluenesulfonic acid, 5.91 g (15.3 mmol, 67%) of the title compound are isolated.
  • 6-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-hexanoic acid 4-hydroxymethyl-2-chloro- phenyl ester Analogously to Example L9, 5.0 g (29.6 mmol) of 4-hydroxymethyl-2-chloro-phenol are reacted with 6.24 g of the compound prepared according to Example L5. After working-up and purification, 5.11 g (14.5 mmol, 49%) of the title compound are isolated.
  • Example ELla 50 mg (78 ⁇ mol) of the compound that is prepared according to Example ELla is dissolved in a mixture of 1.5 ml of trichloromethane and 1.5 ml of dimethylformamide, mixed with 144 mg of the linker that is prepared according to Example L4a, 79 mg of copper(I) chloride, and it is heated for 18 hours to 70°C.
  • the crude mixture is purified by chromatography on thin-layer plates, and 51 mg (62 ⁇ mol, 80%) of the title compound is isolated as a colorless oil.
  • Example EL2 (lS,3S,7S,10R,HS,12S,16R)-[3-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-propyl]- carbamic acid- 10-allyl- 1 l-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5- yl)-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-7-yl ester (A) and (lR,3S,7S,10R,HS,12S,16S)-[3-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-propyl]- carbamic acid- 10-allyl- 11 -hydroxy-8,8, 12, 16-tetramethyl-3-(2-methyl-benzothiazol-5- yl)-5,9-dioxo-4,17-d
  • Example 1 in 2.0 ml of dichloromethane is cooled to -50°C and mixed in portions over a period of 1.5 hours with a total of 1.7 ml of an approximately 0.1 M solution of dimethyl dioxiran in acetone. It is poured into a saturated sodium thiosulfate solution, extracted with dichloromethane, and the combined organic extracts are dried over sodium sulfate. The residue that is obtained after filtration and removal of the solvent is purified by chromatography on thin-layer plates, and 22.7 mg (31.4 ⁇ mol, 50%) of title compound A as well as 7.6 mg (10.5 ⁇ mol, 17%) of title compound B are isolated in each case as a colorless foam.
  • iH-NMR (CDC1 3 ) of A: ⁇ 1.01 (3H), 1.14 (3H), 1.16 (3H), 1.20-1.94 (8H), 1.32 (3H), 2.11-2.74 (9H), 2.82 (IH), 2.84 (3H), 3.30 (2H), 3.48 (2H), 3.68 (IH), 4.36+4.93 (IH), 4.99 (IH), 5.04 (IH), 5.54 (IH), 5.69 (IH), 6.05 (IH), 6.68 (2H), 7.32 (IH), 7.80 (IH), 7.88 (IH) ppm.
  • iH-NMR (CDCI3) of B: ⁇ 1.02 (6H), 1.26 (3H), 1.33 (IH), 1.23-2.27 (12H),
  • Example EL la 50 mg (78 ⁇ mol) of the compound that is prepared according to Example EL la is reacted analogously to Example ELlb with the linker that is produced according to
  • Example L5a and after purification, 39 mg (45.9 ⁇ mol, 59%) of the title compound is isolated as a colorless oil.
  • Example EL3 (4S,7R,8S,9S,13Z,16S)-[5-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-pentyl]-carbamic acid- 7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo- oxacyclohexadec- 13 -en-4-yl ester 84 mg (98.8 ⁇ mol) of the compound that is prepared according to Example EL3a is reacted analogously to Example ELI, and after purification, 43 mg (58.4 ⁇ mol, 59%) of the title compound is isolated as a colorless foam.
  • Example EL4 (lS,3S,7S,10R,llS,12S,16R)-[5-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-pentyl]-carbamic acid- 10-allyl- 11 -hydroxy-8 ,8,12,16-tetramethyl-3 -(2-methyl-benzothiazol-5 -yl)-5 ,9- dioxo-4,17-dioxabicyclo[14.1.0]heptadec-7-yl ester (A) and
  • Example EL5 (4S,7R,8S,9S,13Z,16S)-[10-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-decyl]-carbamic acid-7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6- dioxo-oxacyclohexadec-13-en-4-yl ester
  • EL7a is reacted analogously to Example ELlb with the linker that is produced according to Example L4a, and after purification, 121 mg (147 ⁇ mol, 94%) of the title compound is isolated as a colorless oil.
  • Example EL7b 46 mg (56 ⁇ mol) of the compound that is prepared according to Example EL7b is reacted analogously to Example ELI, and after purification, 17 mg (24 ⁇ mol, 43%) of the title compound is isolated as a colorless foam.
  • H-NMR (CDC1 3 ): ⁇ 0.99-1.30 (2H), 1.03 (3H), 1.07 (3H), 1.21 (3H), 1.51-
  • Example EL7a is reacted analogously to Example ELlb with the linker that is produced according to Example L5a, and after purification, (65.9 ⁇ mol, 42%) of the title compound is isolated as a colorless oil.
  • EL7b is reacted analogously to Example ELI, and after purification, 24.7 mg (33.6 ⁇ mol, 51%) of the title compound is isolated as a colorless foam.
  • iH-NMR (CDCI3): ⁇ 0.97-1.84 (11H), 1.02 (3H), 1.07 (3H), 1.20 (3H), 1.71 (3H), 1.91 (IH), 2.27-2.57 (6H), 2.84 (3H), 2.88 (IH), 2.95 (IH), 3.16 (2H), 3.51 (3H), 4.02 (IH), 4.46+4.83 (IH), 4.94-5.03 (2H), 5.15 (IH), 5.20 (IH), 5.74 (IH), 5.84 (IH), 6.68 (2H), 7.35 (IH), 7.80 (IH), 7.96 (IH) ppm.
  • Example EL 10 0.97-1.84 (11H), 1.02 (3H), 1.07 (3H), 1.20 (3H), 1.71 (3H), 1.91 (IH), 2.27-2.57 (6H), 2.84
  • Example EL9 24.7 mg (33.6 ⁇ mol) of the compound that is prepared according to Example EL9 is reacted analogously to Example EL2, and after purification, 16.7 mg (22.2 ⁇ mol, 66%) of title compound A as well as 2.0 mg (2.7 ⁇ mol, 8%) of title compound B are isolated in each case as a colorless foam.
  • iH-NMR (CDCI3) of A: ⁇ 0.98 (3H), 1.04 (3H), 1.10-1.75 (13H), 1.23 (3H), 1.26 (3H), 2.09-2.62 (6H), 2.75 (IH), 2.84 (3H), 3.15 (2H), 3.51 (2H), 3.57 (IH), 3.99 (IH), 4.08 (IH), 4.46+4.74 (IH), 4.93-5.02 (2H), 5.18 (IH), 5.76 (IH), 6.18 (IH), 6.68 (2H), 7.38 (IH), 7.82 (IH), 7.97 (IH) ppm.
  • iH-NMR (CDCI3) of B: ⁇ 0.83-1.85 (13H), 0.95 (3H), 1.01 (3H), 1.27 (3H),
  • Example ELI 2a in 16 ml of ethyl acetate, is mixed with 51 ⁇ l of triethylamine, 700 mg of the compound that is prepared according to Example L8, and it is stirred for 16 hours at 23°C. It is poured into water, extracted several times with ethyl acetate, the combined organic extracts are washed with saturated sodium chloride solution and dried over magnesium sulfate. The residue that is obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel. 188 mg (219 ⁇ mol, 59%) of the title compound is isolated.
  • Example ELI Analogously to Example ELI, 248 mg (289 ⁇ mol) of the compound that is prepared according to Example EL 12a is reacted, and after working-up and purification, 149 mg (201 ⁇ mol, 69%) of the title compound is isolated.
  • Example EL 14a (4S,7R,8S,9S, 13Z, 16S)-Chloroformic acid-7-allyl-4-(tert-butyl-dimethyl-silanyloxy)- 5,5,9, 13-tetramethyl-l 6-(2-methyI-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec- 13- en-8-yl ester
  • Example EL12a Analogously to Example EL12a, 1.0 g (1.56 mmol) of the compound that is prepared according to Example EL7a is reacted, and 1.05 g (1.49 mmol, 96%) of the title compound is isolated.
  • Example EL 14a in 19 ml of ethyl acetate is mixed with 840 mg of the compound that is prepared according to Example L8, 61.5 ⁇ l of triethylamine, and it is stirred for 16 hours at 23°C. It is mixed with water, extracted several times with ethyl acetate, the combined organic extracts are washed with saturated sodium chloride solution and dried over sodium sulfate. The residue that is obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel. 298 mg (348 ⁇ mol, 79%) of the title compound is isolated.
  • Example EL 15 (lS,3S,7S,10R,l lS,12S,16R)-Carbonic acid-10-allyl-7-hydroxy-8,8,12,16-tetramethyl- 3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-l l-yl ester 4-(2,5-dioxo-2,5-dihydro-pyrrol-l-yl)-phenyl ester
  • Example EL2 Analogously to Example EL2, 67 mg (90 ⁇ mol) of the compound that is prepared according to Example EL 14 is reacted, and after working-up and purification, 32 mg (42 ⁇ mol, 47%) of the title compound is isolated.
  • Example EL 12b Analogously to Example EL 12b, 200 mg (284 ⁇ mol) of the compound that is prepared according to Example EL 12a is reacted with 770 mg of the compound that is prepared according to Example L9, and after working-up and purification, 129 mg (129 ⁇ mol, 45%) of the title compound is isolated.
  • Example EL2 Analogously to Example EL2, 71 mg (80 ⁇ mol) of the compound that is prepared according to Example ELI 8 is reacted, and after working-up and purification, 41 mg (45 ⁇ mol, 57%) of title compound A as well as 12 mg (13 ⁇ mol, 17%) of title compound B are isolated.
  • Example EL2 117 mg (128 ⁇ mol) of the compound that is prepared according to Example EL20 is reacted, and after working-up and purification, 63 mg (68 ⁇ mol, 53%) of title compound A as well as 19 mg (20 ⁇ mol, 16%) of title compound B are isolated.
  • 1H-NMR (CDCI3) of A: ⁇ 1.03 (3H), 1.14 (3H), 1.15 (3H), 1.32 (3H), 1.07-
  • Example EL12b Analogously to Example EL12b, 243 mg (345 ⁇ mol) of the compound that is prepared according to Example EL 12a is reacted with 1.19 g of the compound that is prepared according to Example Ll 1, and after working-up and purification, 171 mg (155 ⁇ mol, 45%) of the title compound is isolated.
  • Example ELI 171 mg (155 ⁇ mol) of the compound that is prepared according to Example EL22a is reacted, and after working-up and purification, 108 mg (110 ⁇ mol, 71%) of the title compound is isolated.
  • iH-NMR (CDC1 3 ): ⁇ 1.02 (3H), 1.14 (6H), 0.88-2.56 (28H), 1.70 (3H), 2.63 (2H), 2.71 (IH), 2.74 (3H), 2.98 (IH), 3.39 (IH), 3.50 (2H), 3.69 (IH), 4.58 (IH), 4.77 (IH), 5.00 (IH), 5.05 (IH), 5.17 (IH), 5.56 (IH), 5.71 (IH), 5.97 (IH), 6.68 (2H), 7.11 (IH), 7.29 (IH), 7.36 (IH), 7.75 (IH), 7.76 (IH), 7.94 (IH) ppm.
  • Example EL2 Analogously to Example EL2, 108 mg (110 ⁇ mol) of the compound that is prepared according to Example EL22 is reacted, and after working-up and purification,
  • Example EL 12b Analogously to Example EL 12b, 271 mg (385 ⁇ mol) of the compound that is prepared according to Example EL14a is reacted with 1.04 g of the compound that is prepared according to Example L9, and after working-up and purification, 193 mg
  • Example EL25 4-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-butanoic acid 4-(lS,3S,7S,10R,l 1S,12S,16R)- [10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo- 4, 17-dioxa-bicyclo [14.1.0]heptadec-l 1 -yloxycarbonyloxymethyl]-2-nitro-phenyl ester (A) and 4-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-butanoic acid 4- (lR,3S,7S,10R,llS,12S,16S)-[10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl- benzothiazol-5-yl)-5,9-di
  • Example EL2 Analogously to Example EL2, 102 mg (115 ⁇ mol) of the compound that is prepared according to Example ELI 9 is reacted, and after working-up and purification, 65 mg (72 ⁇ mol, 63%) of title compound A as well as 3 mg (3.3 ⁇ mol, 3%) of title compound B are isolated.
  • Example EL 12b Analogously to Example EL 12b, 273 mg (387 ⁇ mol) of the compound that is prepared according to Example EL 14a is reacted with 1.12 g of the compound that is prepared according to Example L10, and after working-up and purification, 69 mg (67 ⁇ mol, 17%) of the title compound is isolated.
  • Example ELI 69 mg (67 ⁇ mol) of the compound that is prepared according to Example EL26a is reacted, and after working-up and purification, 26 mg (28 ⁇ mol, 42%) of the title compound is isolated.
  • 1H-NMR (CDC1 3 ): ⁇ 0.93 (3H), 0.95 (3H), 1.16 (3H), 1.60 (3H), 0.98-2.61
  • Example EL2 Analogously to Example EL2, 38 mg (41 ⁇ mol) of the compound that is prepared according to Example EL 19 is reacted, and after working-up and purification, 14 mg (15 ⁇ mol, 37%) of title compound A as well as 2 mg (2 ⁇ mol, 5%) of title compound B are isolated.
  • Example EL28a 1 l-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7- allyl-4-(tert-butyl-dimethyl-silanyloxy)-5,5,9, 13-tetramethyl-l 6-(2-methyl- benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyIoxymethyl]-2- nitro-phenyl ester
  • Example EL12b Analogously to Example EL12b, 273 mg (387 ⁇ mol) of the compound that is prepared according to Example EL14a is reacted with 1.34 g of the compound that is prepared according to Example Ll 1, and after working-up and purification, 196 mg
  • Example ELI Analogously to Example ELI, 196 mg (178 ⁇ mol) of the compound that is prepared according to Example EL28a is reacted, and after working-up and purification, 100 mg (101 ⁇ mol, 57%) of the title compound is isolated.
  • Example EL2 Analogously to Example EL2, 100 mg (101 ⁇ mol) of the compound that is prepared according to Example EL 19 is reacted, and after working-up and purification, 21 mg (21 ⁇ mol, 21%) of title compound A as well as 2 mg (2 ⁇ mol, 2%) of title compound B are isolated.
  • Example EL 12b Analogously to Example EL 12b, 218 mg (309 ⁇ mol) of the compound prepared according to Example EL 12a are reacted with 314 mg of the compound prepared according to Example L12. After working-up and purification, 103 mg (118 ⁇ mol, 35%) of the title compound are isolated.
  • Example EL30 4-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-butanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7- allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo- oxacyclohexadec- 13 -en-4-yloxycarbonyloxymethyl] -phenyl ester
  • Example ELI Analogously to Example ELI, 103 mg (118 ⁇ mol) of the compound prepared according to Example EL30a are reacted. After working-up and purification, 13 mg (15 ⁇ mol, 13%) of the title compound are isolated.
  • Example EL2 Analogously to Example EL2, 13 mg (15 ⁇ mol) of the compound prepared according to Example EL30 are reacted. After working-up and purification, 5.7 mg (6.6 ⁇ mol,
  • Example EL32a 6-(2,5-Dioxo-2,5-dihydro-pyrrol- 1 -yl)-hexanoic acid 4-(4S,7R,8S,9S, 13Z, 16S)-[7- allyl-8-(tert-butyl-dimethyl-silanyloxy)-5,5,9, 13 -tetramethyl- 16-(2-mefhyl- benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec- 13 -en-4-yloxycarbonyloxymethyl]- phenyl ester
  • 218 mg (309 ⁇ mol) of the compound prepared according to Example EL 12a are reacted with 396 mg of the compound prepared according to Example L13. After working-up and purification, 157 mg (159 ⁇ mol, 51%) of the title compound are isolated.
  • Example EL 12b Analogously to Example EL 12b, 218 mg (309 ⁇ mol) of the compound prepared according to Example EL 12a are reacted with 422 mg of the compound prepared according to Example L14. After working-up and purification, 77 mg (73 ⁇ mol, 24%) of the title compound are isolated.
  • Example ELI 77 mg (73 ⁇ mol) of the compound prepared according to Example EL34a are reacted. After working-up and purification, 14 mg (15 ⁇ mol, 20%) of the title compound are isolated.
  • 1H-NMR (CDC1 3 ): ⁇ 0.99 (3H), 1.11 (3H), 1.14 (3H), 0.88-1.88 (22H), 1.70 (3H), 2.24-2.58 (8H), 2.67 (IH), 2.75 (3H), 3.00 (IH), 3.40 (IH), 3.51 (2H), 3.68 (IH), 4.48 (IH), 4.76 (IH), 5.00 (IH), 5.04 (IH), 5.18 (IH), 5.55 (IH), 5.71 (IH), 5.98 (IH), 6.68 (2H), 6.98 (2H), 7.07 (2H), 7.37 (IH), 7.76 (IH), 7.96 (IH) ppm.
  • Example EL35 l l-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic acid 4-(lS,3S,7S,10R,llS,12S, 16R)-[10-allyl-l l-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9- dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-7-yloxycarbonyloxymethyl]-phenyl ester
  • 14 mg ( 15 ⁇ mol) of the compound prepared according to Example EL34 are reacted. After working-up and purification, 6 mg ( 6 ⁇ mol, 42%) of the title compound are isolated.
  • Example EL36 4-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-butanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7- allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo- oxacyclohexadec- 13-en-8-yloxycarbonyloxymethyl]-phenyl ester
  • Example EL36a 4-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-butanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7- allyl-4-(tert-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl- benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]- phenyl ester
  • Example EL12b Analogously to Example EL12b, 330 mg (470 ⁇ mol) of the compound prepared according to Example EL 14a are reacted with 544 mg of the compound prepared according to Example L12. After working-up and purification, 170 mg (178 ⁇ mol,
  • Example EL36 4-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-butanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7- allyl-4-hydroxy-5,5,9, 13 -tetramethyl- 16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo- oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-phenyl ester
  • ELI 170 mg (178 ⁇ mol) of the compound prepared according to Example EL36a are reacted. After working-up and purification, 21 mg (24 ⁇ mol, 14%) of the title compound are isolated.
  • Example ELI 2b Analogously to Example ELI 2b, 450 mg (640 ⁇ mol) of the compound prepared according to Example EL 14a are reacted with 811 mg of the compound prepared according to Example L13. After working-up and purification, 108 mg (110 ⁇ mol,
  • Example EL38 6-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-hexanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7- allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo- oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-phenyl ester 108mg (110 ⁇ mol) of the compound prepared according to Example EL38a in 22 ml dichloromethane are mixed with 1.06 ml (2.74 mmol) of a 20% solution of trifluoroacetic acid in dichloromethane.
  • Example EL2 Analogously to Example EL2, 64 mg (73 ⁇ mol) of the compound prepared according to Example EL38 are reacted. After working-up and purification, 25 mg (28 ⁇ mol, 39%) of the title compound A as well as 5.4 mg (6.1 ⁇ mol, 8.3%) of the title compound B are isolated.
  • Example EL 12b Analogously to Example EL 12b, 450 mg (640 ⁇ mol) of the compound prepared according to Example EL14a are reacted with 992 mg of the compound prepared according to Example L14. After working-up and purification, 67 mg (63 ⁇ mol, 10%) of the title compound are isolated.
  • Example EL38 Analogously to Example EL38, 67 mg (63 ⁇ mol) of the compound prepared according to Example EL40a are reacted. After working-up and purification, 23 mg (24 ⁇ mol,
  • Example EL41 1 l-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic acid 4-(lS,3S,7S,10R,l 1S,12S, 16R)-[10-allyl-7-hydroxy-8,8,l 2, 16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9- dioxo-4, 17-dioxa-bicyclo [14.1.0]heptadec-l l-yloxycarbonyloxymethyl]-phenyl ester (A) and l l-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic acid 4- (1R,3 S,7S, 1 OR, 11 S, 12S, 16S)-[10-allyl-7-hydroxy-8,8, 12, 16-tetramethyl-3-(2-methyl- benzothiazol-5-yl)-5,9
  • Example EL2 Analogously to Example EL2, 33 mg (35 ⁇ mol) of the compound prepared according to Example EL40 are reacted. After working-up and purification, 13 mg (14 ⁇ mol, 38%) of the title compound A as well as 4 mg (4 ⁇ mol, 12%) of the title compound B are isolated.
  • Example EL12b Analogously to Example EL12b, 329 mg (467 ⁇ mol) of the compound prepared according to Example EL12a are reacted with 885 mg of the compound prepared according to Example L15. After working-up and purification, 126 mg (127 ⁇ mol,
  • Example EL12b Analogously to Example EL12b, 329 mg (467 ⁇ mol) of the compound prepared according to Example EL 12a are reacted with 821 mg of the compound prepared according to Example L16. After working-up and purification, 120 mg (118 ⁇ mol,
  • Example EL2 Analogously to Example EL2, 60 mg (66 ⁇ mol) of the compound prepared according to Example EL44 is reacted. After working-up and purification, 32 mg (34.7 ⁇ mol, 53%) of the title compound A as well as 11 mg (11.9 ⁇ mol, 18%) of the title compound B are isolated.
  • Example EL 12b Analogously to Example EL 12b, 323 mg (459 ⁇ mol) of the compound prepared according to Example EL 12a are reacted with 790 mg of the compound prepared according to Example L17. After working-up and purification, 96 mg (8$ ⁇ mol, 19%) of the title compound are isolated.
  • Example ELI Analogously to Example ELI, 59 mg (54 ⁇ mol) of the compound prepared according to Example EL46a are reacted. After working-up and purification, 27 mg (27.7 ⁇ mol,
  • Example EL47 1 l-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic acid 4-(lS,3S,7S,10R,l 1S-12S, 16R)-[10-allyl-ll-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9- dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-7-yloxycarbonyloxymethyl]-2-chloro- phenyl ester (A) and ll-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic acid 4- (lR,3S,7S,10R,l lS,12S,16S)-[10-allyl-l l-hydroxy-8,8,12,16-tetramethyl-3-(2- methyl-benzothia
  • Example EL2 Analogously to Example EL2, 27 mg (27 ⁇ mol) of the compound prepared according to Example EL46 are reacted. After working-up and purification, 14 mg (14.1 ⁇ mol, 52%) of the title compound A as well as 5 mg (5.0 ⁇ mol, 19%) of the title compound B are isolated.
  • Example EL12b Analogously to Example EL12b, 340 mg (482 ⁇ mol) of the compound prepared according to Example EL14a are reacted with 885 mg of the compound prepared according to Example L15. After working-up and purification, 151 mg (152 ⁇ mol,
  • Example ELI 2b Analogously to Example ELI 2b, 340 mg (482 ⁇ mol) of the compound prepared according to Example EL14a are reacted with 848 mg of the compound prepared according to Example L16. After working-up and purification, 158 mg (155 ⁇ mol,
  • Example EL2 Analogously to Example EL2, 58 mg (64 ⁇ mol) of the compound prepared according to Example EL50 are reacted. After working-up and purification, 25 mg (27 ⁇ mol, 42%) of the title compound A as well as 7 mg (7.6 ⁇ mol, 12%) of the title compound B are isolated.
  • Example EL 12b Analogously to Example EL 12b, 355 mg (476 ⁇ mol) of the compound prepared according to Example EL 14a are reacted with 790 mg of the compound prepared according to Example L17. After working-up and purification, 122 mg (112 ⁇ mol, 24%) of the title compound are isolated.
  • Example ELI Analogously to Example ELI, 122 mg (112 ⁇ mol) of the compound prepared according to Example EL52a are reacted. After working-up and purification, 28 mg
  • Example EL2 Analogously to Example EL2, 28 mg (29 ⁇ mol) of the compound prepared according to Example EL52 are reacted. After working-up and purification, 6.2 g (6.3 ⁇ mol, 22%) of the title compound A as well as 0.3 mg (0.3 ⁇ mol, 1%) of the title compound B are isolated.
  • Example EL54a (4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-8-(tert-butyl-dimethyl-silanyloxy)- 5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13- en-4-yl ester 4-amino-benzyl ester
  • Example ELI 2b Analogously to Example ELI 2b, 160 mg (227 ⁇ mol) of the compound prepared according to Example EL 12a are reacted with 191 mg (4-amino-3-nitro-phenyl)- methanol. After working-up and purification, 51 mg (61 ⁇ mol, 27%) of the title compound are isolated.
  • Example EL54 (4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-8-hydroxy-5,5,9,l 3-tetramethyl-l 6-(2- methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec- 13-en-4-yl ester 4-[4-(2,5- dioxo-2,5-dihydro-pyrrol-l-yl)-butyrylamino]-3-nitro-benzyl ester
  • ELI 101 mg (101 ⁇ mol) of the compound prepared according to Example EL54a are reacted. After working-up and purification, 62 mg (70 ⁇ mol, 69%) of the title compound are isolated.
  • Example EL54b Analogously to Example EL54b, 50 mg (60 ⁇ mol) of the compound prepared according to Example EL54a are reacted with the compound prepared according to Example L5. After working-up and purification, 58 mg (56 ⁇ mol, 94%) of the title compound are isolated.
  • Example EL57 (1S,3S,7S,10R,1 lS,12S,16R)-Carbonic acid 10-allyl- 1 l-hydroxy-8,8,12,16- tetramethyl-3 -(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4, 17-dioxa- bicyclo[14.1.0]heptadec-7-yl ester 4-[6-(2,5-dioxo-2,5-dihydro-pyrrol-l-yl)- hexanoylamino]-3-nitro-benzyl ester (A) and (1R,3S,7S,10R,11S,12S,16S)-Carbonic acid 10-allyl-l 1 -hydroxy-8,8, 12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9- dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec
  • Example EL2 Analogously to Example EL2, 34 mg (37 ⁇ mol) of the compound prepared according to Example EL56 are reacted. After working-up and purification, 19 mg (20.4 ⁇ mol, 55%) of the title compound A as well as 6 mg (6.4 ⁇ mol, 17%) of the title compound B are isolated.
  • Example EL54b Analogously to Example EL54b, 130 mg (156 ⁇ mol) of the compound prepared according to Example EL54a are reacted with the compound prepared according to Example L6. After working-up and purification, 120 mg (109 ⁇ mol, 70%) of the title compound are isolated.
  • Example EL58 (4S,7R,8S,9S, 13Z, 16S)-Carbonic acid 7-allyl-8-hydroxy-5,5,9, 13-tetramethyl-l 6-(2 ⁇ methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yl ester 4-[l l-(2,5- dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoylamino]-3-nitro-benzyl ester
  • 120 mg (109 ⁇ mol) of the compound prepared according to Example EL58a are reacted. After working-up and purification, 89 mg (90 ⁇ mol, 83%) of the title compound are isolated.
  • Example EL60a (4S,7R,8S,9S, 13Z, 16S)-Carbonic acid 7-allyl-8-(tert-butyl-dimethyl-silanyloxy)- 5,5,9,13 -tetramethyl- 16-(2-methyl-benzothiazol-5 -yl)-2,6-dioxo-oxacyclohexadec- 13- en-4-yl ester 6-(2,5-dioxo-2,5-dihydro-pyrrol-l-yl)-hexyl ester
  • Example ELI 2b 1.25 g (1.77 mmol) of the compound prepared according to Example EL 12a are reacted with 1.75 g of the compound prepared according to L18. After working-up and purification, 119 mg (138 ⁇ mol, 8%) of the title compound are isolated.
  • Example ELI Analogously to Example ELI, 101 mg (117 ⁇ mol) of the compound prepared according to Example EL60a are reacted. After working-up and purification, 68 mg (91 ⁇ mol, 77%) of the title compound are isolated.
  • Example EL2 Analogously to Example EL2, 68 mg (91 ⁇ mol) of the compound prepared according to Example EL60 are reacted. After working-up and purification, 26 mg (34 ⁇ mol,
  • Example ELI Analogously to Example ELI, 145 mg (145 ⁇ mol) of the compound prepared according to Example EL62a are reacted. After working-up and purification, 67 mg
  • Example EL2 Analogously to Example EL2, 67 mg (76 ⁇ mol) of the compound prepared according to Example EL62 are reacted. After working-up and purification, 37 mg (41 ⁇ mol, 54%) of the title compound A as well as 12 mg (13 ⁇ mol, 18%) of the title compound B are isolated.
  • Example EL64a (4S,7R,8S,9S, 13Z, 16S)-Carbonic acid 7-allyl-4-(tert-butyl-dimethyl-silanyloxy)- 5 ,5 ,9, 13 -tetramethyl- 16-(2-methyl-benzothiazol-5 -yl)-2,6-dioxo-oxacyclohexadec- 13 - en-8-yl ester 4-[4-(2,5-dioxo-2,5-dihydro-pyrrol-l-yl)- hexanoylamino]-3-nitro-benzyl ester
  • 140 mg (167 ⁇ mol) of the compound prepared according to Example EL62a are reacted with the compound prepared according to Example L5. After working-up and purification, 155 mg (150 ⁇ mol, 90%) of the title compound are isolated.
  • Example EL54b Analogously to Example EL54b, 140 mg (167 ⁇ mol) of the compound prepared according to Example EL62a are reacted with the compound prepared according to Example L6. After working-up and purification, 165 mg (150 ⁇ mol, 90%) of the title compound are isolated.
  • Example ELI Analogously to Example ELI, 145 mg (132 ⁇ mol) of the compound prepared according to Example EL66a are reacted. After working-up and purification, 106 mg
  • Example EL2 Analogously to Example EL2, 106 mg (108 ⁇ mol) of the compound prepared according to Example EL66 are reacted. After working-up and purification, 58 mg (58 ⁇ mol, 54%) of the title compound A as well as 6 mg (6 ⁇ mol, 6%) of the title compound B are isolated.
  • ED-B fibronectin domain B
  • the solution of 661 ⁇ g of tri(2-carboxyethyl)phosphine- hydrochloride in 236 ⁇ l of PBS is mixed with the solution of 1.54 mg of AP39 in 1.12 ml of PBS, and it is incubated for 1.5 hours at 25°C. Desalination is done with a pre- equilibrated ⁇ AP-5 column at a concentration of 450 ⁇ l of AP39r and 50 ⁇ l of PBS. After elution with 1 ml of PBS, the reduced antibody fragment AP39r is isolated in a concentration of 0.7 mg/ml.
  • Example ELE1 Analogously to Example ELE1, the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate that is prepared according to Example ELI 1, and the solution of the title compounds is isolated.
  • the dilution factor relative to the antibody fragment is approximately 2.5. m/z (Calc): 26347.3 m/z (exp.): 26358 ⁇ 20
  • Example ELE1 Analogously to Example ELE1, the antibody fragment that is reduced according to Example ELEla is reacted with effector-linker conjugate A that is prepared according to Example ELI 6, and the solution of the title compound is isolated.
  • the dilution factor relative to the antibody fragment is approximately 2.5. m/z (Calc): 26173 m/z (exp.): 26174 ⁇ 20
  • Example ELE1 Analogously to Example ELE1, the antibody fragment that is reduced according to Example ELEla is reacted with effector-linker conjugate A that is prepared according to Example ELI 7, and the solution of the title compound is isolated.
  • the dilution factor relative to the antibody fragment is approximately 2.5. m/z (Calc): 26174 m/z (exp.): 26163 ⁇ 20
  • Example ELE1 3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-ll-yl ester 4-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-l-yl)-phenyl ester
  • Example ELE1 the antibody fragment that is reduced according to Example ELEla is reacted with effector-linker conjugate A that is prepared according to Example ELI 5, and the solution of the title compound is isolated.
  • the dilution factor relative to the antibody fragment is approximately 2.5.
  • Example ELEl Analogously to Example ELEl, the antibody fragment that is reduced according to Example ELEla is reacted with effector-linker conjugate A that is prepared according to Example EL19, and the solution of the title compound is isolated.
  • the dilution factor relative to the antibody fragment is approximately 2.5. m/z (Calc): 26383 m z (exp.): 26377 ⁇ 20
  • Example ELEl Analogously to Example ELEl, the antibody fragment that is reduced according to Example ELEl a is reacted with effector-linker conjugate A that is prepared according to Example EL25, and the solution of the title compound is isolated.
  • the dilution factor relative to the antibody fragment is approximately 2.5. m/z (Calc): 26383 m z (exp.): 26381 ⁇ 20
  • Example ELEl Analogously to Example ELEl, the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL21, and the solution of the title compound is isolated.
  • the dilution factor relative to the antibody fragment is approximately 2.5. m/z (Calc.) : 26411 m/z (exp.): 26384 ⁇ 30 m/z (Calc.) : 25673 m/z (exp.): 25657 ⁇ 20 (6-(3-(AP39r)-sulfanyl-2,5-dioxo- pyrrolidin-l-yl)-hexanoic acid fragment)
  • Example ELEl Analogously to Example ELEl, the antibody fragment that is reduced according to
  • Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL23 and the solution of the title compound is isolated.
  • the dilution factor relative to the antibody fragment is approximately 2.5. m/z (Calc.) : 26482 m/z (exp.): 26477 ⁇ 20 m/z (Calc.) : 25744 m/z (exp.): 26752 ⁇ 20 (l l-(3-(AP39r)-sulfanyl-2,5-dioxo- pyrrolidin-l-yl)-undecanoic acid fragment)
  • Example ELEl (1 S,3 S,7S, 1 OR, 11 S, 12S, 16R)-[10-allyl-7-hydroxy-8,8, 12, 16-tetramethyl-3-(2-methyl- benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-ll- yloxycarbonyloxymethyl]-2-nitro-phenyl ester
  • Example ELEl Analogously to Example ELEl, the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL27 and the solution of the title compound is isolated.
  • the dilution factor relative to the antibody fragment is approximately 2.5.
  • Example ELEl Analogously to Example ELEl, the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL29 and the solution of the title compound is isolated.
  • the dilution factor relative to the antibody fragment is approximately 2.5.
  • m z (Calc.) 26482 m/z (exp.): 26491 ⁇ 20 m/z (Calc.) : 25744 m/z (exp.): 25757 ⁇ 20 (l l-(3-(AP39r)-sulfanyl-2,5-dioxo- pyrrolidin-l-yl)-undecanoic acid fragment)
  • Example ELEl Analogously to Example ELEl, the antibody fragment that is reduced according to
  • Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL31 and the solution of the title compound is isolated.
  • the dilution factor relative to the antibody fragment is approximately 2.5. m z (Calc.) : 26338 m/z (exp.): 26304 ⁇ 30
  • Example ELEl Analogously to Example ELEl, the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL33 and the solution of the title compound is isolated.
  • the dilution factor relative to the antibody fragment is approximately 2.5. m/z (Calc.) : 26366 m/z (exp.): 26347 ⁇ 30
  • Example ELE 19
  • Example ELEl Analogously to Example ELEl, the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL35 and the solution of the title compound is isolated.
  • the dilution factor relative to the antibody fragment is approximately 2.5. m z (Calc.) : 26437 m/z (exp.): 26412 ⁇ 30
  • Example ELEl Analogously to Example ELEl, the antibody fragment that is reduced according to
  • Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL37 and the solution of the title compound is isolated.
  • the dilution factor relative to the antibody fragment is approximately 2.5. m/z (Calc.) : 26338 m/z (exp.): 26338 ⁇ 20
  • Example ELEl Analogously to Example ELEl, the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL39 and the solution of the title compound is isolated.
  • the dilution factor relative to the antibody fragment is approximately 2.5. m/z (Calc.) : 26366 m/z (exp.): 26384 ⁇ 30
  • Example ELE22
  • Example ELEl Analogously to Example ELEl, the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL41 and the solution of the title compound is isolated.
  • the dilution factor relative to the antibody fragment is approximately 2.5. m/z (Calc.) : 26437 m/z (exp.): 26421 ⁇ 30
  • Example ELEl Analogously to Example ELEl, the antibody fragment that is reduced according to
  • Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL43 and the solution of the title compound is isolated.
  • the dilution factor relative to the antibody fragment is approximately 2.5. m/z (Calc.) : 26373 m/z (exp.): 26358 ⁇ 20 m z (Calc.) : 25645 m z (exp.): 25627 ⁇ 20 (4-(3-(AP39r)-sulfanyl-2,5-dioxo- pyrrolidin-l-yl)-butanoic acid fragment)
  • Example ELEl Analogously to Example ELEl, the antibody fragment that is reduced according to
  • Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL45 and the solution of the title compound is isolated.
  • the dilution factor relative to the antibody fragment is approximately 2.5. m/z (Calc.) : 26401 m/z (exp.): 26395 ⁇ 20
  • Example ELEl Analogously to Example ELEl, the antibody fragment that is ' reduced according to Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL49 and the solution of the title compound is isolated.
  • the dilution factor relative to the antibody fragment is approximately 2.5. m/z (Calc.) : 26373 m/z (exp.): 26341 ⁇ 30
  • Example ELEl Analogously to Example ELEl, the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL51 and the solution of the title compound is isolated.
  • the dilution factor relative to the antibody fragment is approximately 2.5. m z (Calc.) : 26401 m/z (exp.): 26391 ⁇ 20
  • Example ELEl (1 S,3 S,7S, 1 OR, 11 S, 12S, 16R)-[ 10-allyl-7-hydroxy-8,8, 12, 16-tetramethyl-3-(2-methyl- benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-l l- yloxycarbonyloxymethyl] -2-chlor-phenyl ester
  • the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL53 and the solution of the title compound is isolated.
  • the dilution factor relative to the antibody fragment is approximately 2.5. m/z (Calc.) : 26471 m/z (exp.): 26466 ⁇ 20
  • Example ELEl Analogously to Example ELEl, the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL55 and the solution of the title compound is isolated.
  • the dilution factor relative to the antibody fragment is approximately 2.5. m/z (Calc) : 26337 m/z (exp.): ⁇ 20
  • Example ELEl Analogously to Example ELEl, the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL57 and the solution of the title compound is isolated.
  • the dilution factor relative to the antibody fragment is approximately 2.5. m/z (Calc.) : 26365 m/z (exp.): ⁇ 20
  • Example ELEl Analogously to Example ELEl, the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL61 and the solution of the title compound is isolated.
  • the dilution factor relative to the antibody fragment is approximately 2.5. m/z (Calc.) : 26246 m/z (exp.): ⁇ 20

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Abstract

L'invention concerne des conjugués d'épothilones et des dérivés d'épothilone (en tant qu'effecteurs) avec des biomolécules adéquates (en tant qu'unités de reconnaissance). Le procédé de production consiste à faire réagir les effecteurs avec des lieurs appropriés ; les composés qui sont produits étant conjugués avec les unités de reconnaissance. La présente invention concerne également l'utilisation pharmaceutique de ces conjugués pour traiter des troubles prolifératifs ou associés à l'angiogenèse.
EP03743752A 2002-07-31 2003-07-31 Nouveaux conjugues d'effecteurs, procedes permettant de les produire et utilisation pharmaceutique de ceux-ci Withdrawn EP1524979A2 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
DE10234975A DE10234975A1 (de) 2002-07-31 2002-07-31 Neue Effektor-Konjugate, Verfahren zu ihrer Herstellung und ihre pharmazeutische Verwendung
DE10234975 2002-07-31
DE10305098 2003-02-07
DE10305098A DE10305098A1 (de) 2003-02-07 2003-02-07 Neue Effektor-Konjugate, Verfahren zu ihrer Herstellung und ihre pharmazeutische Verwendung
US45167303P 2003-03-05 2003-03-05
US451673P 2003-03-05
PCT/EP2003/008483 WO2004012735A2 (fr) 2002-07-31 2003-07-31 Nouveaux conjugues d'effecteurs, procedes permettant de les produire et utilisation pharmaceutique de ceux-ci

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NO20051038L (no) 2005-04-06
AU2003253365A1 (en) 2004-02-23
HRP20050186A2 (en) 2005-10-31
MXPA05001282A (es) 2005-04-28
CA2492437A1 (fr) 2004-02-12
IS7708A (is) 2005-02-23
WO2004012735A3 (fr) 2004-05-27
BR0313043A (pt) 2005-06-14
ECSP055626A (es) 2005-04-18
NZ537870A (en) 2007-03-30
WO2004012735A2 (fr) 2004-02-12
CO5700741A2 (es) 2006-11-30
PL374528A1 (en) 2005-10-31
IL166039A0 (en) 2006-01-15
JP2006505627A (ja) 2006-02-16
KR20050026033A (ko) 2005-03-14

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