WO2004012735A2 - New effector conjugates, process for their production and their pharmaceutical use - Google Patents

New effector conjugates, process for their production and their pharmaceutical use Download PDF

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Publication number
WO2004012735A2
WO2004012735A2 PCT/EP2003/008483 EP0308483W WO2004012735A2 WO 2004012735 A2 WO2004012735 A2 WO 2004012735A2 EP 0308483 W EP0308483 W EP 0308483W WO 2004012735 A2 WO2004012735 A2 WO 2004012735A2
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WIPO (PCT)
Prior art keywords
dione
dihydroxy
tetramethyl
methyl
oxacyclohexadec
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PCT/EP2003/008483
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French (fr)
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WO2004012735A3 (en
Inventor
Markus Berger
Gerhard Siemeister
Ulrich Klar
Jörg WILLUDA
Andreas Menrad
Klaus Bosslet
Original Assignee
Schering Ag
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Publication date
Priority claimed from DE10234975A external-priority patent/DE10234975A1/en
Priority claimed from DE10305098A external-priority patent/DE10305098A1/en
Priority to NZ537870A priority Critical patent/NZ537870A/en
Priority to MXPA05001282A priority patent/MXPA05001282A/en
Priority to EA200500223A priority patent/EA200500223A1/en
Priority to AU2003253365A priority patent/AU2003253365A1/en
Priority to JP2005506073A priority patent/JP2006505627A/en
Priority to EP03743752A priority patent/EP1524979A2/en
Application filed by Schering Ag filed Critical Schering Ag
Priority to BR0313043-6A priority patent/BR0313043A/en
Priority to YUP-2005/0082A priority patent/RS20050082A/en
Priority to CA002492437A priority patent/CA2492437A1/en
Priority to IL16603903A priority patent/IL166039A0/en
Publication of WO2004012735A2 publication Critical patent/WO2004012735A2/en
Publication of WO2004012735A3 publication Critical patent/WO2004012735A3/en
Priority to IS7708A priority patent/IS7708A/en
Priority to NO20051038A priority patent/NO20051038L/en
Priority to HR20050186A priority patent/HRP20050186A2/en

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    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • 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
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    • 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

Abstract

Conjugates of epothilones and epothilone derivatives (as effectors) with suitable biomolecules (as recognition units) are described. Their production is carried out by the effectors being reacted with suitable linkers, and the compounds that are produced are conjugated to the recognition units. The pharmaceutical use of the conjugates for treating proliferative or angiogenesis-associated processes is described.

Description

New Effector Conjugates, Process for their Production and their Pharmaceutical
Use
The development of the understanding relating to the recognition of binding regions, especially in the field of monoclonal antibodies or fragments thereof against specific tumor antigens, makes it possible to consider a selective tumor therapy by specific release of an anti-tumor active agent at the target site.
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.
The successful therapy of solid tumors, especially with monoclonal antibodies, 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. In comparison to tumor cells, 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. Within the scope of this invention, surprisingly enough, 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,
1. to find a method to link highly active active agents from the structural class of the epothilones and epothilone derivatives to suitable linkers,
2. to synthesize suitable linkers,
3. to develop a method to link these epothilone-linker conjugates to recognition units, such as, for example, monoclonal antibodies or fragments thereof, to form immune conjugates that are both chemically and metabolically sufficiently stable for the development of a pharmaceutical, and that are superior to the epothilones or epothilone derivatives that are taken as a basis with respect to their therapeutic range, their selectivity of action and/or undesirable toxic side effects and/or the degree of their activity.
This invention accordingly comprises effector conjugates of general formula I
Figure imgf000003_0001
in which R.la, 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, R2b5 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, and R4a R4bs independently of one another, are hydrogen, CJ-CJO alkyl, aryl, aralkyl, or together a -(CH2)p group, in which p is 2 to 5, R5 is hydrogen, C 1 -C 10 alkyl, aryl, aralkyl, CO2H, CC^alkyl, CH2OH,
CH2OAlkyl, CH2OAcyl, CN, CH NH2, CH2N(alkyl, acyl)ι?2, or
CH2Hal, 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,
D-E is a group H2C-CH2, HC=CH, C≡C, CH(OH)-CH(OH), CH(OH)-CH2,
O
CH2-CH(OH), HC~CH , O-CH2, or, if G represents a CH2 group, D-E is CH -O,
W is a group C(=X)R^, or a bi- or tricyclic aromatic or heteroaromatic radical,
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 is hydrogen or C 1 -C \ Q alkyl, X is an oxygen atom, or two OR2^ groups, or a C2-C \ 0 alkylenedioxy group that may be straight-chain or branched, or H/OR9, or a CRIORI 1 group, R8 is hydrogen, C^-Ci 0 alkyl, aryl, aralkyl, halogen or CN, and R9 is hydrogen or a protective group PG-^,
RiO, 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^,
A- Y can represent a group O-C(=O), O-CH , CH2-C(=O), NR21 -C(=O) or
NR21-SO2, R20 can represent C1-C20 alkyl, R21 can represent a hydrogen atom or C \ -C \ Q alkyl,
PGX, PGY, and PG^ can represent a protective group PG, and L1, L2, and \ , independently of one another, can represent hydrogen, a group C(=O)Cl, a group C(=S)C1, a group PG^ or a linker of general formula (III) or (IN); provided that at least one substituent L1, L2 or L4 represents a linker of general formula (III) or (IN); the linker of general formula (III) has the following structure,
Figure imgf000005_0001
in which
T can represent oxygen or sulfur,
U can represent oxygen, CHR22, CHR22-NR 3-C(=O , CHR22-NR23- C(=S , O-C(=O)-CHR 2-NR23-C(=O)-, O-C(=O)-CHR22-NR23-
C(=S)- orNR24a, o can represent 0 to 15,
V can represent a bond, aryl, a group
NR24b-C(=O)-O-(CH2)s-^^ __
or a group
N
Figure imgf000006_0001
s can represent 0 to 4,
Q can represent a bond, O-C(=O)-NR2 c, O-C(-S)-NR24c,
Figure imgf000006_0002
R22 can represent hydrogen, C -C \ Q alkyl, aryl or aralkyl, R23 can represent hydrogen or C \ -C \ Q alkyl,
R24a, R24^, and R24c, independently of one another, can represent hydrogen or
Ci-Cio alkyl, q can represent 0 to 15,
Figure imgf000007_0001
II
° , or CO2H; and the linker of general formula (IN) has the following structure,
Figure imgf000007_0002
in which
T can represent oxygen or sulfur,
W1, W2 are the same or different and can represent oxygen or ΝR2 a, o can represent 0 to 5,
R 22 can represent hydrogen, Ci-C10 alkyl, aryl or aralkyl,
R 23 can represent hydrogen, or C1-C10 alkyl,
R 24a can represent hydrogen or C^ o alkyl,
R27 can represent halogen, CΝ, ΝO2, CO2R28, or OR28,
R28 can represent hydrogen, CJ-CKJ alkyl, aryl or aralkyl,
q can represent 0 to 5, u can represent oxygen, CHR , 22
Figure imgf000007_0003
CHR )2 -NτrR>23
C(=S)- or - o alkyl, r can represent 0 to 20, FG1 can represent -CK) alkyl-S3,
Figure imgf000008_0001
as a single isomer or a mixture of different isomers and/or as a pharmaceutically acceptable salt thereof.
In addition, 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 FG1 is replaced by a group FG a or FG , wherein FG2 or FG2b can have the following meanings:
Figure imgf000008_0002
FG2b: -CONH- and wherein a recognition unit is conjugated via a sulfur atom with the group FG2a, wherein the indicated sulfur atom is a component of the recognition unit, or via an amide function of group FG2b, 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 spiegelmer, a recombinant protein, a framework structure, a monoclonal antibody or a fragment of a monoclonal antibody.
According to this invention, 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.
The effector recognition unit conjugates according to the invention can be used in the form of their α-, β- or γ-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. For example, 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.
The production of 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 02/32844, WO 02/14323, and WO 02/8440.
As alkyl groups Rl* Rlb, R a, R2b R3, R.4a R4b R5; R85 RW Rl 1, R205 R21, R22, R23, R 4a, R2 , R24c, R25 and R26, 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 R2a R2b R3, R4a, R4b R55 R8^ R103 Rl 1, R20? R21? R22, R23, R24 R24b, R24c R25 a^ R26 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).
As aryl radicals Rl , Rib, R2a R2b R3; R4a R4b R5} R8; R10s R11, R22,
R2^ 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, CO2H, CO2-alkyl, -ΝH2, -NO2, -N3, -CN, C1-C20-alkyl, C1-C20-acyl or C1-C20- acyloxy groups, are suitable. The 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. As 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 more places by halogen, OH, O- alkyl, CO H, CO -alkyl, -NH , -NO2, -N3, -CN, C1-C2o-alkyl, Cι-C2o- cyl or C^ C20_acyl°χy groups, are suitable. The heteroatoms can be oxidized provided that this does not cause the aromatic character to be lost, such as, for example, the oxidation of a quinolyl to a quinolyl-N-oxide.
The aralkyl groups in Rla, R b, R2 R2b R3, R4a R4b R5, R8? R105 Rlls R22 and R2^ 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. As 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,
Figure imgf000010_0001
Cl-C20_acyl or Cι-C2υ- cylo y groups.
As representatives of protective groups PG, tris(Cj-C20 alkyl)silyl, bis(Cj-C20 alkyl)-arylsilyl, (C1-C20 alkyl)-diarylsilyl, tris(aralkyl)-silyl, Cι-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, Cι-C20-alkoxycarbonyl, C1-C20- alkylsulfonyl as well as arylsulfonyl can be cited.
As alkyl-, silyl- and acyl radicals for the protective groups PG, especially the radicals that are known to one skilled in the art are considered. Preferred are the alkyl or silyl radicals that can be easily cleaved from the corresponding alkyl and silyl ethers, such as, for example, the methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert.- butyldimethylsilyl, tert.-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl, benzyl, para-nitrobenzyl, and para-methoxybenzyl radicals, as well as alkylsulfonyl and arylsulfonyl radicals. As an alkoxycarbonyl radical, e.g., trichloroethyloxycarbonyl (Troc) is suitable. As an 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. As amino protective groups PG, the radicals that are known to one skilled in the art are suitable. For example, the Alloc, Boc, Z, benzyl, f-Moc, Troc, stabase or benzostabase group can be mentioned.
As halogen atoms, fluorine, chlorine, bromine or iodine can be considered. The acyl groups can contain 1 to 20 carbon atoms, formyl, acetyl, propionyl, isopropionyl and pivalyl groups being preferred.
The C2-Cιo~ah yleιιe-α,ω-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
O-C(=O) or NR2l-C(=O); D-E represents an H2C-CH2 group; G represents a CH2 group; Z represents an oxygen atom; Rla Rib in each case represent CI-CJO ^kyl or together a -(CH2)p group with p equal to 2 or 3 or 4; R2a, R2b, independently of one another, represent hydrogen, CI-CJO alkyl, C2-C10 alkenyl, or C2-C10 alkynyl; R3 represents hydrogen; R4a, R4b, independently of one another, represent hydrogen or C^-CJO alkyl; R5 represents hydrogen, or C1-C4 alkyl or CH2OH or CH2NH2 or CH2N(alkyl, acyl) j 2 or CH2Hal; R^ and R? together represent an additional bond or together an NH group or together an N-alkyl group or together a CH2 group or together an oxygen atom; W represents a group C(=X)R^ or a 2-methylbenzothiazol-5-yl radical or a 2- methylbenzoxazol-5-yl radical or a quinolin-7-yl radical or a 2- aminomethylbenzothiazol-5-yl radical or a 2-hydroxymethylbenzothiazol-5-yl radical or a 2-aminomethylbenzoxazol-5-yl radical or a 2-hydroxymethylbenzoxazol-5-yl radical; 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-yl or hydrogen 2-aminomethyloxazol-4-yl or hydrogen 2-hydroxymethylthiazol-4-yl or hydrogen/2-hydroxymethyloxazol-4-yl. As linkers of general formula (III), compounds are preferred in which V represents a bond or an aryl radical, o is equal to zero, and T represents an oxygen atom.
As linkers of general formula (III), in addition compounds are preferred in which V represents a bond or an aryl radical or a group
; Q represents a bond or a group
Figure imgf000011_0001
; and o is 0 to 4. Especially preferred are compounds of general formula (III), wherein N represents a bond or a group
; Q represents a bond or a group
Figure imgf000012_0001
; o is equal to 0, 2 or 3; s is equal to 1; and T is an oxygen atom. As 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
1 00
(IN), wherein o is 0, 2 or 3; W is an oxygen atom; q is equal to 0; R is hydrogen, C\ -C3 alkyl or aralkyl; R23 is hydrogen or -C3 alkyl; R24ais hydrogen or Ct -C3 alkyl; R27 is fluorine, chlorine, CΝ, ΝO2 , CO2R28 or OR28 ; R28 is hydrogen or d -C5 alkyl; and U is oxygen, CHR22 or CHR22-NR23-C(=O)-.
As recombinant proteins for use as recognition units, for example, binding regions derived from antibodies, so-called CDRs, are suitable.
As framework structures for use as recognition units, for example, high- molecular structures that are not derived from antibodies are suitable. For example, structures of the fibronectin type 3 and of crystallins can be mentioned.
As 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.
As preferred 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.
As 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
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
As especially preferred recognition units for treating hematological tumors, 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.
As especially preferred recognition units for anti-angiogenic therapy, antibodies or fragments thereof, such as NCAM, CD31, ELAM, endoglin, NEGFRI/II, αvβ3, 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:
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentametl yl-16-[l- methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4- yl)- 1 -methyl-vinyl] -5,5,7,9,13 -pentamethyl-oxacyclohexadec- 13 -ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-Aminomethyl-thiazol-4-yl)-l-methyl- vinyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione,
(lS,3S(E),7S,10R,l lS,12S,16R)-7,l l-Dihydroxy-8,8,10,12,16-pentamethyl-3- [l-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane- 5,9-dione,
(lS,3S(E),7S,10R,l lS,12S,16R)-7,l l-Dihydroxy-3-[2-(2-hydroxymethyl- thiazol-4-yl)- 1 -methyl-vinyl]-8,8, 10, 12, 16-pentamethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione, (lS,3S(E),7S,10R,llS,12S,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-l-methyl- vinyl]-7, 11 -dihydroxy-8,8, 10, 12, 16-pentamethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione,
(4S,7R,8S,9S, 13Z,16S(E))-4,8-Dihydroxy-7-ethyl-5,5,9, 13-tetramethyl-l 6-[l - methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4- yl)-l-methyl-vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-Aminomethyl-thiazol-4-yl)-l-methyl- vinyl]-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione, (lS,3S(E),7S,10R,HS,12S,16R)-7,ll-Dihydroxy-10-ethyl-8,8,12,16- tetramethyl-3-[l-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa- bicyclo [14.1.0]heptadecane-5 ,9-dione,
(lS,3S(E),7S,10R,llS,12S,16R)-7,ll-Dihydroxy-3-[2-(2-hydroxymethyl- thiazol-4-yl)- 1 -methyl-vinyl] - 10-ethyl-8 ,8 , 12,16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]hepta-decane-5,9-dione, (lS,3S(E),7S,10R,l lS,12S,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-l-methyl- vinyl]-7, 11 -dihydroxy- 10-ethyl-8,8, 12,16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]hepta-decane-5,9-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[l- fluoro-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4- yl)- 1 -fluoro-vinyl]-5 ,5 ,7,9, 13 -pentamethyl-oxacyclohexadec- 13-ene-2,6-dione, (4S,7R,8S,9S, 13Z, 16S(Z))- 16-[2-(2-Aminomethyl-thiazol-4-yl)-l -fluoro- vinyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione,
(lS,3S(Z),7S,10R,l lS,12S,16R)-7,l l-Dihydroxy-8,8,10,12,16-pentamethyl-3- [l-fluoro-2-(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-[2-(2-hydroxymethyl- thiazol-4-yl)-l -fluoro-vinyl]-8,8, 10, 12, 16-pentamethyl-4, 17-dioxa- bicyclo [14.1.0]heptadecane-5 ,9-dione,
(1 S,3 S(Z),7S, 1 OR, 11 S, 12S,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-l -fluoro- vinyl]-7, 11 -dihydroxy-8,8, 10, 12, 16-pentamethyl-4, 17-dioxa- bicyclo [14.1.0]heptadecane-5 ,9-dione,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[l- chloro-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4- yl)-l-chloro-vinyl]-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-thiazol-4-yl)-l-chloro- vinyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione,
(lS,3S(Z),7S,10R,l lS,12S,16R)-7,l l-Dihydroxy-8,8,10,12,16-pentamethyl-3- [ 1 -chloro-2-(2-methyl-thiazol-4-yl)-vinyl] -4, 17-dioxa-bicyclo [14.1.0]heptadecane-5 ,9- dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-[2-(2-hydroxymethyl- thiazol-4-yl)-l-chloro-vinyl]-8,8,10,12,16-pentamethyl-4,17-dioxa- bicyclo [14.1.0]heptadecane-5 ,9-dione,
(lS,3S(Z),7S,10R,llS,12S,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-l-chloro- vinyl]-7,l 1 -dihydroxy-8,8, 10, 12, 16-pentamethyl-4, 17-dioxa- bicyclo[l 4.1.0]heptadecane-5,9-dione,
(4S,7R,8S,9S, 13Z, 16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9, 13-tetramethyl-l 6-[l - fluoro-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8S,9S, 13Z, 16S(Z))-4,8-Dihydroxy-l 6-[2-(2-hydroxymethyl-thiazol-4- yl)-l-fluoro-vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione,
(4S,7R,8S,9S,13Z, 16S(Z))- 16-[2-(2-Aminomethyl-thiazol-4-yl)-l -fluoro- vinyl]-4,8-dihydroxy-7-ethyl-5,5,9, 13-tetramethyl-oxacyclohexadec- 13-ene-2,6-dione, (lS,3S(Z),7S,10R,HS,12S,16R)-7,l l-Dihydroxy-10-ethyl-8,8,12,16- tetramethyl-3-[l -fluoro-2-(2-methyl-thiazol-4-yl)-vinyl]-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione,
(1 S,3 S(Z),7S, 1 OR, 11 S, 12S, 16R)-7, 1 l-Dihydroxy-3-[2-(2-hydroxymethyl- thiazol-4-yl)- 1 -fluoro-vinyl]- 10-ethyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]hepta-decane-5,9-dione,
(1 S,3S(Z),7S, 1 OR, 11 S, 12S,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-l -fluoro- vinyl] -7, 11 -dihydroxy- 10-ethyl-8 , 8 , 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]hepta-decane-5,9-dione,
(4S,7R,8S,9S, 13Z, 16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9, 13-tetramethyl-l 6-[l - chloro-2-(2-methyl-thiazol-4-yl)-vinyl] -oxacyclohexadec- 13 -ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4- yl)- 1 -chloro-vinyl] -7-ethyl-5 ,5 ,9, 13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-thiazol-4-yl)-l-chloro- vinyl]-4,8-dihydroxy-7-efhyl-5,5,9, 13 -tetramethyl-oxacyclohexadec- 13-ene-2,6-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-10-ethyl-8,8,12,16- tetramethyl-3 -[ 1 -chloro-2-(2-methyl-thiazol-4-yl)-vinyl] -4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione,
(1 S,3S(Z),7S, 10R,11 S, 12S, 16R)-7, 11 -Dihydroxy-3-[2-(2-hydroxymethyl- thiazol-4-yl)- 1 -chloro-vinyl]- 10-ethyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]hepta-decane-5,9-dione,
(lS,3S(Z),7S,10R,l lS,12S,16R)-3-[2-(2-Aminomefhyl-thiazol-4-yl)-l-chloro- vinyl]-7, 11 -dihydroxy- 10-ethyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]hepta-decane-5 ,9-dione,
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[l- methyl-2-(2-pyridyl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione,
(lS,3S(E),7S,10R,llS,12S,16R)-7,ll-Dihydroxy-8,8,10,12,16-pentamethyl-3- [l-methyl-2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[l- methyl-2-(2-pyridyl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione,
(lS,3S(E),7S,10R,HS,12S,16R)-7,l l-Dihydroxy-10-ethyl-8,8,12,16- tetramethyl-3-[l-methyl-2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane- 5,9-dione,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[l- fluoro-2-(2-pyridyl)-viny 1] -oxacyclohexadec- 13 -ene-2,6-dione,
(lS,3S(Z),7S,10R,l lS,12S,16R)-7,l l-Dihydroxy-8,8,10,12,16-pentamethyl-3- [l-fluoro-2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[l- chloro-2-(2-pyridyl)-vinyl]-oxacyclohexadec- 13 -ene-2,6-dione,
(lS,3S(Z),7S,10R,llS,12S,16R)-7,l l-Dihydroxy-8,8,10,12,16-pentamethyl-3- [l-chloro-2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[l- fluoro-2-(2-pyridyl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione,
(lS,3S(Z),7S,10R,HS,12S,16R)-7,l l-Dihydroxy-10-ethyl-8,8,12,16- tetramethyl-3 - [ 1 -fluoro-2-(2-pyridyl)- vinyl] -4, 17-dioxa-bicyclo [14.1.0]heptadecane- 5,9-dione,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[l- chloro-2-(2-pyridyl)-vinyl] -oxacyclohexadec- 13 -ene-2,6-dione,
(lS,3S(Z),7S,10R,llS,12S,16R)-7,ll-Dihydroxy-10-ethyl-8,8,12,16- tetramethyl-3-[l -chloro-2-(2-pyridyl)-vinyl]-4, 17-dioxa-bicyclo[14.1.0]heptadecane- 5,9-dione,
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[l- methyl-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione,
(4S,7R,8S,9S, 13Z, 16S(E))-4,8-Dihydroxy-l 6-[2-(2-hydroxymethyl-oxazol-4- yl)- 1 -methyl-vinyl] -5,5,7,9,13 -pentamethyl-oxacyclohexadec- 13 -ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-Aminomethyl-oxazol-4-yl)-l-methyl- vinyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione, (1S,3S(E),7S,10R,11S,12S,16R)-7,11 -Dihydroxy-8,8, 10, 12,16-pentamethyl-3-
[1 -methyl-2-(2-methyl-oxazol-4-yl)-vinyl]-4, 17-dioxa-bicyclo[14.1.0]heptadecane- 5,9-dione, (lS,3S(E),7S,10R,HS,12S,16R)-7,l l-Dihydroxy-3-[2-(2-hydroxymethyl- oxazol-4-yl)- 1 -methyl- vinyl]-8,8, 10, 12, 16-pentamefhyl-4, 17-dioxa- bicyclo [14.1.0]heptadecane-5 ,9-dione,
(lS,3S(E),7S,10R,llS,12S,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-l-methyl- vinyl]-7,l l-dihydroxy-8,8,10,12,16-ρentamethyl-4,17-dioxa- bicyclof 14.1.0]heptadecane-5 ,9-dione,
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[l- methyl-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4- yl)-l-methyl-vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-Aminomethyl-oxazol-4-yl)-l-methyl- vinyl]-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione,
(lS,3S(E),7S,10R,HS,12S,16R)-7,ll-Dihydroxy-10-ethyl-8,8,12,16- tetramethyl-3 - [ 1 -methyl-2-(2-methyl-oxazol-4-yl)-vinyl] -4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione,
(lS,3S(E),7S,10R,l lS,12S,16R)-7,l l-Dihydroxy-3-[2-(2-hydroxymethyl- oxazol-4-yl)- 1 -methyl- vinyl]- 10-ethyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]hepta-decane-5,9-dione,
( 1 S,3 S(E),7S, 1 OR, 11 S, 12S, 16R)-3-[2-(2- Aminomethyl-oxazol-4-yl)- 1 -methyl- vinyl]-7, 11 -dihydroxy- 10-ethyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]hepta-decane-5,9-dione,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[l- fluoro-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4- yl)-l-fluoro-vinyl]-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-oxazol-4-yl)-l-fluoro- vinyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione,
(lS,3S(Z),7S,10R,llS,12S,16R)-7,l l-Dihydroxy-8,8,10,12,16-pentamethyl-3- [l-fluoro-2-(2-methyl-oxazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dione,
(lS,3S(Z),7S,10R,llS,12S,16R)-7,l l-Dihydroxy-3-[2-(2-hydroxymethyl- oxazol-4-yl)-l -fluoro-vinyl]-8,8, 10, 12, 16-pentamethyl-4,l 7-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione, (lS,3S(Z),7S,10R,llS,12S,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-l-fluoro- vinyl]-7, 11 -dihydroxy-8,8, 10, 12, 16-pentamethyl-4, 17-dioxa- bicyclo[l 4.1.0]heptadecane-5,9-dione,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[l- chloro-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4- yl)-l-chloro-vinyl]-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-oxazol-4-yl)-l-chloro- vinyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione, (lS,3S(Z),7S,10R,llS,12S,16R)-7,l l-Dihydroxy-8,8,10,12,16-pentamethyl-3-
[l-chloro-2-(2-methyl-oxazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dione,
(lS,3S(Z),7S,10R,HS,12S,16R)-7,l l-Dihydroxy-3-[2-(2-hydroxymethyl- oxazol-4-yl)- 1 -chloro-vinyl]-8,8, 10, 12, 16-pentamethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione,
(lS,3S(Z),7S,10R,llS,12S,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-l-chloro- vinyl]-7, 11 -dihydroxy-8,8, 10, 12, 16-pentamethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5 ,9-dione,
(4S,7R,8S,9S, 13Z, 16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9, 13-tetramethyl-l 6-[l - fluoro-2-(2-methyl-oxazol-4-yl)-vinyl] -oxacyclohexadec- 13 -ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4- yl)- 1 -fluoro-vinyl] -7-ethyl-5 ,5 ,9, 13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-oxazol-4-yl)-l-fluoro- vinyl]-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione, (lS,3S(Z),7S,10R,llS,12S,16R)-7,l l-Dihydroxy-10-ethyl-8,8,12,16- tetramethyl-3 - [ 1 -fluoro-2-(2-methyl-oxazol-4-yl)-vinyl]-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione,
(lS,3S(Z),7S,10R,llS,12S,16R)-7,l l-Dihydroxy-3-[2-(2-hydroxymethyl- oxazol-4-yl)- 1 -fluoro-vinyl]-l 0-ethyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]hepta-decane-5 ,9-dione,
(lS,3S(Z),7S,10R,llS,12S,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-l-fluoro- vinyl]-7, 11 -dihydroxy- 10-ethyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]hepta-decane-5 ,9-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[l- chloro-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4- yl)-l -chloro-vinyl]-7-ethyl-5,5,9, 13-tetramethyl-oxacyclohexadec- 13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-oxazol-4-yl)-l-chloro- vinyl]-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione,
(lS,3S(Z),7S,10R,HS,12S,16R)-7,l l-Dihydroxy-10-ethyl-8,8,12,16- tetramefhyl-3 - [ 1 -chloro-2-(2-methyl-oxazol-4-yl)-vinyl] -4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-[2-(2-hydroxymethyl- oxazol-4-yl)- 1 -chloro-vinyl]- 10-ethyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]hepta-decane-5,9-dione,
(lS,3S(Z),7S,10R,l lS,12S,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-l-chloro- vinyl]-7, 11 -dihydroxy- 10-ethyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]hepta-decane-5,9-dione,
(4S,7R,8S,9S, 13Z,16S(E))-4,8-Dihydroxy-5,5,7,9, 13-pentamethyl-l 6-[2-(2- methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4- yl)-vinyl] -5,5,7,9,13 -pentamethyl-oxacyclohexadec- 13 -ene-2,6-dione, (4S,7R,8S,9S, 13Z, 16S(E))-16-[2-(2-Aminomethyl-thiazol-4-yl)-vinyl]-4,8- dihydroxy-5 ,5,7,9,13 -pentamethyl-oxacyclohexadec- 13 -ene-2,6-dione,
(lS,3S(E),7S,10R,llS,12S,16R)-7,l l-Dihydroxy-8,8,10,12,16-pentamethyl-3- [2-(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione, (lS,3S(E),7S,10R,llS,12S,16R)-7,ll-Dihydroxy-3-[2-(2-hydroxymethyl- thiazol-4-yl)-vinyl]-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane- 5,9-dione,
(1 S,3S(E),7S, 10R,11 S, 12S, 16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-vinyl]- 7, 11 -dihydroxy-8,8,10, 12, 16-pentamethyl-4,l 7-dioxa-bicyclo[l 4.1.0]heptadecane-5,9- dione, (4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[2-
(2-mefhyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4- yl)-vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8S59S,13Z,16S(E))-16-[2-(2-Aminomethyl-thiazol-4-yl)-vinyl]-4,8- dihydroxy-7-ethyl-5 ,5,9,13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione,
(lS,3S(E),7S,10R,HS,12S,16R)-7,l l-Dihydroxy-10-ethyl-8,8,12,16- tetramethyl-3 - [2-(2-methyl-thiazol-4-yl)-vinyl] -4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione,
(1 S,3 S(E),7S,1 OR, 11 S, 12S,16R)-7, 11 -Dihydroxy-3-[2-(2-hydroxymethyl- thiazol-4-yl)-vinyl]- 10-ethyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione,
(1 S,3 S(E),7S, 1 OR, 11 S, 12S, 16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-vinyl]- 7, 11 -dihydroxy- 10-ethyl-8,8, 12,16-tetramethyl-4, 17-dioxa- bicyclo [14.1.0]heptadecane-5,9-dione,
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[2-(2- pyridyl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione,
(lS,3S(E),7S,10R,llS,12S,16R)-7,l l-Dihydroxy-8,8,10,12,16-pentamethyl-3- [2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione,
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[2- (2-pyridyl)- vinyl] -oxacyclohexadec- 13 -ene-2,6-dione,
(lS,3S(E),7S,10R,HS,12S,16R)-7,ll-Dihydroxy-10-ethyl-8,8,12,16- tetramethyl-3-[2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione, (4S,7R,8S,9S, 13Z,16S)-4,8-Dihydroxy-5,5,7,9, 13-pentamethyl-l 6-(2-methyl- benzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5- yl)-5 ,5 ,7,9, 13 -pentamethyl-oxacyclohexadec- 13 -ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy- 5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione,
(lS,3S,7S,10R,llS,12S,16R)-7,ll-Dihydroxy-8,8,10,12,16-pentamethyl-3-(2- methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione,
(1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-(2-hydroxymethyl- benzothiazol-5-yl)-8,8, 10, 12,16-pentamethyl-4, 17-dioxa-bicyclo [ 14.1.0]heptadecane- 5,9-dione,
(lS,3S,7S,10R,llS,12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,ll- dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dione, (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-(2- methyl-benzothiazol-5-yl)-oxacyclohexadec- 13 -ene-2,6-dione,
(4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy-l 6-(2-hydroxymethyl-benzothiazol-5- yl)-7-ethyl-5 ,5,9,13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione, (4S,7R,8S,9S, 13Z, 16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy-
7-ethyl-5 ,5 ,9, 13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione,
(lS,3S,7S,10R,l lS,12S,16R)-7,l l-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl- 3 -(2-methyl-benzothiazol-5 -yl)-4, 17-dioxa-bicyclo [14.1.0]heptadecane-5 ,9-dione,
(lS,3S,7S,10R,l lS,12S,16R)-7,ll-Dihydroxy-3-(2-hydroxymethyl- benzothiazol-5 -yl)- 10-ethyl-8 , 8, 12,16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione,
(1 S,3S,7S, 1 OR, 11 S, 12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7, 11 - dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dione, (4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy-7-propyl-5,5,9, 13-tetramethyl-l 6-(2- methyl-benzothiazol-5-yl)-oxacyclohexadec- 13 -ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5- yl)-7-propyl-5 ,5,9,13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy- 7-propyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione,
(lS,3S,7S,10R,HS,12S,16R)-7,l l-Dihydroxy-10-propyl-8,8,12,16- tetramethyl-3-(2-methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane- 5,9-dione,
(1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-(2-hydroxymethyl- benzothiazol-5-yl)- 10-propyl-8,8, 12,16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione,
(1 S,3S,7S, 1 OR, 11 S, 12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7, 11 - dihydroxy- 10-propyl-8,8, 12, 16-tetramethyl-4, 17-dioxa-bicyclo [ 14.1.0]heptadecane- 5,9-dione, (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-butyl-5,5,9,13-tetramethyl-16-(2- methyl-benzothiazol-5-yl)-oxacyclohexadec- 13-ene-2,6-dione,
(4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy-l 6-(2-hydroxymethyl-benzothiazol-5- yl)-7-butyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroχy- 7-butyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione,
(lS,3S,7S,10R,llS,12S,16R)-7,ll-Dihydroxy-10-butyl-8,8,12,16-tetramethyl- 3 -(2-methyl-benzothiazol-5 -yl)-4, 17-dioxa-bicyclo [14.1.0]heptadecane-5 ,9-dione, (1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-(2-hydroxymethyl- benzothiazol-5-yl)- 10-butyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione,
(lS,3S,7S,10R,llS,12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,ll- dihydroxy-10-butyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dione,
(4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy-7-allyl-5,5,9,l 3-tetramethyl-l 6-(2- methyl-benzothiazol-5-yl)-oxacyclohexadec- 13 -ene-2,6-dione,
(4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy-l 6-(2-hydroxymethyl-benzothiazol-5- yl)-7-allyl-5 ,5 ,9, 13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy-
7-allyl-5 ,5 ,9, 13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione,
(lS,3S,7S,10R,llS,12S,16R)-7,ll-Dihydroxy-10-allyl-8,8,12,16-tetramethyl- 3-(2-methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-(2-hydroxymethyl- benzothiazol-5-yl)-10-allyl-8,8,12,16-tetramethyl-4,17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione,
(lS,3S,7S,10R,llS,12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,ll- dihydroxy-10-allyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dione, (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-prop-2-inyl-5,5,9,13-tetramethyl-16-
(2-methyl-benzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione,
(4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy-l 6-(2-hydroxymethyl-benzothiazol-5- yl)-7-prop-2-inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy- 7-prop-2-inyl-5 ,5,9,13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione,
(lS,3S,7S,10R,HS,12S,16R)-7,ll-Dihydroxy-10-prop-2-inyl-8,8,12,16- tetramethyl-3-(2-methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane- 5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-(2-hydroxymethyl- benzothiazol-5-yl)- 10-prop-2-inyl-8,8, 12, 16-tetramethyl-4,l 7-dioxa- bicyclo[14.1.0]heptadecane-5 ,9-dione,
(lS,3S,7S,10R,llS,12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,ll- dihydroxy- 10-prop-2-inyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione,
(4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy-7-but-3 -enyl-5,5 ,9, 13 -tetramethyl- 16- (2-methyl-benzothiazol-5-yl)-oxacyclohexadec- 13 -ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5- yl)-7-but-3-enyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy- 7-but-3 -enyl-5 ,5 ,9, 13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione,
(lS,3S,7S,10R,HS,12S,16R)-7,ll-Dihydroxy-10-but-3-enyl-8,8,12,16- tetramethyl-3-(2-methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane- 5,9-dione,
(1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-(2-hydroxymethyl- benzothiazol-5-yl)- 10-but-3-enyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione,
(1 S,3S,7S, 1 OR, 11 S, 12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7, 11 - dihydroxy- 10-but-3-enyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione,
(4S,7R,8S,9S, 13Z,16S)-4,8-Dihydroxy-7-but-3-inyl-5,5,9, 13 -tetramethyl- 16- (2-methyl-benzothiazol-5-yl)-oxacyclohexadec- 13 -ene-2,6-dione,
(4S,7R,8 S,9S, 13Z, 16S)-4,8-Dihydroxy- 16-(2-hydroxymethyl-benzothiazol-5- yl)-7-but-3-inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy- 7-but-3-inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione,
(lS,3S,7S,10R,HS,12S,16R)-7,ll-Dihydroxy-10-but-3-inyl-8,8,12,16- tetramethyl-3-(2-methyl-benzothiazol-5-yl)-4, 17-dioxa-bicyclo [14.1.Ojheptadecane- 5,9-dione,
(1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-(2-hydroxymethyl- benzothiazol-5-yl)-10-but-3-inyl-8,8,12,16-tetramethyl-4,17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione, (lS,3S,7S,10R,l lS,12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,ll- dihydroxy- 10-but-3 -inyl- 8,8,12,16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione,
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-(2-methyl- benzoxazol-5-yl)-oxacyclohexadec- 13-ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5- yl)-5 ,5 ,7,9, 13 -pentamethyl-oxacyclohexadec- 13 -ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy- 5 ,5 ,7,9, 13 -pentamethyl-oxacyclohexadec- 13 -ene-2,6-dione, (1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-8,8,10,12,16-pentamethyl-3-(2- methyl-benzoxazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-(2-hydroxymethyl- benzoxazol-5-yl)-8,8, 10,12,16-pentamethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane- 5,9-dione, (1S,3S,7S,10R,1 lS,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,l 1- dihydroxy-8,8, 10, 12, 16-pentamethyl-4, 17-dioxa-bicyclo [14.1.0]heptadecane-5,9- dione,
(4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy-7-ethyl-5,5,9, 13 -tetramethyl- 16-(2- methyl-benzoxazol-5 -yl)-oxacyclohexadec- 13 -ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5- yl)-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione,
(4S,7R,8S,9S, 13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy- 7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione,
(lS,3S,7S,10R,llS,12S,16R)-7,ll-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl- 3-(2-methyl-benzoxazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione, (1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-(2-hydroxymethyl- benzoxazol-5-yl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa- bicyclo [14.1.0]heptadecane-5 ,9-dione,
(lS,3S,7S,10R,l lS,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,ll- dihydroxy- 10-ethyl-8,8, 12,16-tetramethyl-4, 17-dioxa-bicyclo [ 14.1.0]heptadecane-5,9- dione,
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-propyl-5,5,9,13-tetramethyl-16-(2- methyl-benzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5- yl)-7-propyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy- 7-propyl-5 ,5 ,9, 13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione, (lS,3S,7S,10R,HS,12S,16R)-7,l l-Dihydroxy-10-propyl-8,8,12,16- tetramethyl-3 -(2-methyl-benzoxazol-5 -yl)-4, 17-dioxa-bicyclo [14.1.0]heptadecane-5 ,9- dione,
(1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-(2-hydroxymethyl- benzoxazol-5-yl)- 10-propyl-8,8, 12,16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione,
(lS,3S,7S,10R,l lS,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,l l- dihydroxy- 10-propyl-8,8, 12, 16-tetramethyl-4, 17-dioxa-bicyclo[l 4.1.0]heptadecane- 5,9-dione,
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-butyl-5,5,9,13-tetramethyl-16-(2- methyl-benzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5- yl)-7-butyl-5 ,5 ,9, 13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione,
(4S,7R,8S,9S, 13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy- 7-butyl-5 ,5 ,9, 13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione, (1S,3S,7S,10R,11S,12S,16R)-7,11 -Dihydroxy- lO-butyl-8,8, 12,16-tetramethyl-
3-(2-methyl-benzoxazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione,
(1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-(2-hydroxymethyl- benzoxazol-5-yl)- 10-butyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione, (lS,3S,7S,10R,llS,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,l l- dihydroxy- 10-butyl-8,8, 12, 16-tetramethyl-4, 17-dioxa-bicyclo[ 14.1.0]heptadecane-5,9- dione,
(4S,7R,8S,9S, 13Z,16S)-4,8-Dihydroxy-7-allyl-5,5,9, 13 -tetramethyl- 16-(2- methyl-benzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5- yl)-7-allyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy- 7-allyl-5,5 ,9, 13 -tetramethyl-oxacyclohexadec- 13-ene-2,6-dione, (lS,3S,7S,10R,llS,12S,16R)-7,ll-Dihydroxy-10-allyl-8,8,12,16-tetramethyl- 3 -(2-methyl-benzoxazol-5-yl)-4, 17-dioxa-bicyclo [ 14.1.0]heptadecane-5 ,9-dione,
(1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dmydroxy-3-(2-hydroxymethyl- benzoxazol-5-yl)- 10-allyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione,
(lS,3S,7S,10R,llS,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,l l- dihydroxy-10-allyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dione,
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-proρ-2-inyl-5,5,9,13-tetramethyl-16- (2-methyl-benzoxazol-5-yl)-oxacyclohexadec- 13 -ene-2,6-dione,
(4S,7R,8S,9S, 13Z,16S)-4,8-Dihydroxy-l 6-(2-hydroxymethyl-benzoxazol-5- yl)-7-prop-2-inyl-5 ,5 ,9, 13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione,
(4S,7R,8S,9S, 13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy- 7-prop-2-inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione, (lS,3S,7S,10R,HS,12S,16R)-7,ll-Dihydroxy-10-prop-2-inyl-8,8,12,16- tetramethyl-3-(2-methyl-benzoxazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dione,
(1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-(2-hydroxymethyl- benzoxazol-5-yl)- 10-prop-2-inyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5 ,9-dione,
(1 S,3S,7S,10R,11 S, 12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7, 11 - dihydroxy-10-prop-2-inyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione,
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-but-3-enyl-5,5,9,13-tetramethyl-16- (2-methyl-benzoxazol-5 -yl)-oxacyclohexadec- 13 -ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5- yl)-7-but-3 -enyl-5 ,5 ,9, 13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy- 7-but-3 -enyl-5 ,5 ,9, 13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione, (lS,3S,7S,10R,HS,12S,16R)-7,ll-Dihydroxy-10-but-3-enyl-8,8,12,16- tetramethyl-3-(2-methyl-benzoxazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dione, (1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-(2-hydroxymethyl- benzoxazol-5-yl)- 10-but-3-enyl-8,8, 12,16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione,
(lS,3S,7S,10R,HS,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,l l- dihydroxy- 10-but-3-enyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo [14.1.0]heptadecane-5 ,9-dione,
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-but-3-inyl-5,5,9,13-tetramethyl-16- (2-mefhyl-benzoxazol-5 -yl)-oxacyclohexadec- 13 -ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5- yl)-7-but-3 -inyl-5 ,5 ,9, 13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione,
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy- 7-but-3-inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione,
(lS,3S,7S,10R,l lS,12S,16R)-7,ll-Dihydroxy-10-but-3-inyl-8,8,12,16- tetramethyl-3-(2-methyl-benzoxazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dione,
(1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-(2-hydroxymethyl- benzoxazol-5-yl)- 10-but-3 -inyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo [14.1.0]heptadecane-5 ,9-dione,
(lS,3S,7S,10R,llS,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,ll- dihydroxy-10-but-3-inyl-8,8,12,16-tetramethyl-4,17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione.
In a compound of general formula (I) according to the invention that contains one of the above-mentioned elements, the hydrogen atoms in the above-mentioned elements are replaced in the positions indicated in formula (I) by radicals L -L3, wherein radicals L!-L3 have the above-indicated meanings.
The invention also relates to linkers of general formula III
RG1 (CH2)— V— (CH2)— FG1 HP ,
in which
RG1 can be an O=C=N group or an S=C=N group, and o, V, q and FG! have the meanings that are already mentioned above, as well as linkers of general formula III2 RG2 (CH2)— V— (CH2)q— FG1 |||2, in which
RG2 can be a Hal-C(=T)-CHR22 group or a Hal-C(=T)-CHR22-NR23-C(=T) group or an R 6-C(=O)-O-C(-T)-CHR22 group or an R26-C(=O)-O-C(=T)-CHR22- NR23-C(=T) group; R26 can be Cχ-Cιo 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
RG3 (CH2)0— V— (CH2)q— FG1 Up,
in which RG3 can be an OH group or an NHR24a 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 (IN1):
Figure imgf000039_0001
in which
RG1 is an O=C=Ν group or an S=C=N group, and o, q, r, W2, R27, U and FG1 have the meanings that are mentioned in claim 1; or linkers of general formula (IN2):
Figure imgf000039_0002
in which RG2 is a Hal-C(=T)-CHR22 group or a Hal-C(=T)-CHR 2-NR23-C(=T) group or an R26-C(=O)-O-C(=T)-CHR22 group or an R26-C(=O)-O-C(=T)-CHR22-NR23- C(=T) group, wherein R2^ is Cχ-Cχo alkyl, aryl, or aralkyl, and R22, R23, T, o, q, r, W2, R27, U and FG1 have the meanings that are mentioned in claim 1 ; i or linkers of general formula (IN3):
Figure imgf000040_0001
in which
RG3 is an OH group or an ΝHR24a group or a COOH group, and R24a, o, q, r, W2, R27, U and FG1 have the meanings that are mentioned in claim 1. According to the invention, 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.
In addition, linkers of general formulas III1, III2 or III3 according to the invention are preferred, in which V represents a bond or an aryl radical or a group
Figure imgf000040_0002
; Q represents a bond or a group
-O-C(=O)-NR24c— T \
; and o is 0 to 4. Especially preferred from the above are those linkers in which V represents a bond or a group
NR24b-C(=O)-O-(CH2)s-^~^ _
^ ; Q represents a bond or a group
-O-C(=O)-NR24C-H ~^
; o is equal to 0, 2 or 3; s is equal to 1; and T is an 0 oxygen atom.
In addition, preferred according to the invention are linkers of general formulas
IN , IN or IN , in which o is zero to four and q is zero to three. Especially preferred from the above are those linkers in which o is 0, 2 or 3; W1 is an oxygen atom; q is equal to 0; R22 is hydrogen, CrC3 alkyl or aralkyl; R23 is hydrogen or C C3 alkyl; R24a is hydrogen or d-C3 alkyl; R27 is fluorine, chlorine, CN, NO2, CO2R28 or OR28; R2S is hydrogen or Cj-C5 alkyl; and U is oxygen, CHR22 or CHR22-NR23-C(=O). Additionally, the invention relates to methods to react a linker of general formula III1 or IN1 with a compound of general formula I, in which the condition that at least one group Ll , L2 or L4 represent a linker need not be met, and in which Ll and/or L2 and/or L4 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 III2 or IN2 with a compound of general formula I, in which the condition that at least one group Ll , L2 or l represent a linker need not be met, and Ll and/or L2 and/or \β 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 III3 or IN3 with a compound of general formula I, in which the condition that at least one group Ll , L2 or \ represent a linker need not be met, and Ll and/or L2 and/or l have the meaning of a C(=O)Hal group or a C(=S)Hal group, and free hydroxyl groups and/or amino groups that are not required for the reaction are optionally protected.
The invention also relates to the use of a compound of general formula I, wherein the substituents have the above-mentioned meanings, but the condition that at least one substituent L1, L2 or L4 represents a linker of general formula III or IN need not be met, and at least one substituent L1, L2 or L4 represents hydrogen, a group C(=O)Cl, or a group C(S)C1 , in a method as described above.
The invention also relates to the use of a compound of general formula I, wherein the substituents have the above-mentioned meanings, but the condition that at least one substituent L1, L2 or L4 represent a linker of general formula III or IN need not be met, and at least one substituent L1, L2 or L4 represents hydrogen, a group C(=O)Cl, or a group C(S)C1, for the production of an effector recognition unit conjugate as described above. The invention also relates to the use of a linker of general formula III1, III2, III3,
IN1, IN2 or IN3 for the production of an effector conjugate, as described above. 1 0 "λ
The invention also relates to the use of a linker of general formula III , III , III ,
1 0 ^
IN , IN or IN for the production of an effector recognition unit conjugate as described above.
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.
Examples of the Synthesis of Linkers (L)
Example Ll
(S) 2- [(3 -Methyltrisulfanyl-propionyl)-methyl-amino] -propanoic acid
Example Ll a
(S) 2- [(3 -Acetylsulfanyl-propionyl)-methyl-amino] -propanoic acid ethyl ester
The solution of 15 g (89.5 mmol) of N-methylalanine ethyl ester-hydrochloride in 850 ml of anhydrous tetrahydrofuran is mixed at 23°C with 4.1 g of an approximately 60% sodium hydride dispersion and, after 3 hours, with 23.5 g of 3- acetylsulfanyl-propanoic acid chloride. It is allowed to react for two days, mixed with saturated sodium bicarbonate solution, and extracted several times with ethyl acetate.
The combined organic extracts are washed with saturated sodium chloride solution, dried over sodium sulfate, and the residue that is obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel. 17.6 g (67.3 mmol,
75%) of the title compound is isolated as a colorless oil.
Example Lib
(S) 2-[(3-Mercapto-propionyl)-methyl-amino]-propanoic acid The solution of 17.6 g (67.3 mmol) of the compound prepared according to
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. By adding 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 Lie
(S) 2- [(3 -Mercapto-propionyl)-methyl-amino] -propanoic acid methyl ester The solution of 4.53 g (maximum 23.7 mol) of the crude product, prepared according to Example Lib, in 135 ml of diethyl ether is esterified at 0°C with an ethereal solution of diazomethane. After removal of the solvent, 4.59 g (22.4 mmol, 94%) of the title compound is isolated as a pale yellow oil, which 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 Ll (S) 2-[(3-Methyltrisulfanyl-propionyl)-methyl-amino]-propanoic acid
The solution of 10 g (35.3 mmol) of the compound, prepared according to
Example Lid, in 20 ml of ethanol is mixed with 1 1 of phosphate puffer with a pH of
7, pig liver esterase, and it is incubated at 27°C for 46 hours. By adding a 4N hydrochloric acid, the pH is adjusted to 1, it is extracted with dichloromethane, dried over sodium sulfate, and after filtration and removal of the solvent, 8.3 g (30.8 mmol,
87%) of the title compound is isolated as a colorless oil, which is reacted without further purification.
1H-NMR (CDC13): δ = 1.43+1.51 (3H), 2.55+2.63 (3H), 2.87 (2H), 2.88+3.00
(3H), 3.08-3.26 (2H), 4.63+5.19 (IH), 7.90 (IH) ppm.
Example L2
[(3 -Methyltrisulfanyl-propionyl)-methyl-amino] -acetic acid
Example L2a 2-[(3-Acetylsulfanyl-propionyl)-methyl-amino]-acetic acid ethyl ester
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
[(3 -Mercapto-propionyl)-methyl-amino] -acetic acid
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 L2c [(3 -Mercapto-propionyl)-methyl-amino] -acetic acid methyl ester
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 L2d
[(3 -Methyltrisulfanyl-propionyl)-methyl-amino] -acetic acid methyl ester
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 L2 [(3-Methyltrisulfanyl-propionyl)-methyl-amino]-acetic acid
2.00 g (7.83 mmol) of the compound that is prepared according to Example L2d is reacted analogously to Example Ll, and 0.64 g (2.51 mmol, 32%) of the title compound is isolated as a colorless oil. iH-NMR (CDC13): δ = 2.41+2.56 (3H), 2.61-3.27 (7H), 3.98 (2H), 4.38 (IH) ppm.
Example L3 (S) 2-[(3-Methyltrisulfanyl-propionyl)-methyl-amino]-3-phenyl-propionic acid Example L3a
(S) 2-[(3-Acetylsulfanyl-propionyl)-methyl-amino]-3-phenyl-propanoic acid ethyl ester
7.73 g (31.7 mmol) of N-methylphenylalanine ethyl ester-hydrochloride is reacted analogously to Example Lla, and 2.3 g (6.82 mmol, 22%) of the title compound is isolated as a colorless oil.
Example L3b
(S) 2- [(3 -Mercapto-propionyl)-methyl-amino] -3 -phenyl-propanoic acid 1.09 g (3.23 mmol) of the compound that is prepared according to Example
L3a is reacted analogously to Example Lib, and 0.744 g (2.78 mmol, 86%) 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
(S) 2- [(3 -Methyltrisulfanyl-propionyl)-methyl-amino] -3 -phenyl-propanoic acid methyl ester
0.77 g (2.74 mmol) of the compound that is prepared according to Example
L3c is reacted analogously to Example Lid, and 0.72 g (2.00 mmol, 73%) of the title compound is isolated as a colorless oil.
Example L3
(S) 2- [(3 -Methyltrisulfanyl-propionyl)-methyl-amino] -3 -phenyl-propanoic acid
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 L4 4-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-butanoic acid
20.0 g (193.9 mmol) of 4-aminobutyric acid is mixed with 19 g of maleic acid anhydride, 290 ml of acetic acid, and it is heated for 4 hours in an oil bath at 130°C. It is azeotropically concentrated by evaporation with repeated addition of toluene, the residue is dissolved in dichloromethane and purified by chromatography on fine silica gel. 17.1 g (93.4 mmol, 48%) of the title compound is isolated as a crystalline solid. 1H-NMR (CDCI3): δ = 1.93 (2H), 2.38 (2H), 3.60 (2H), 6.71 (2H) ppm.
Example L4a l-(3-Isocyanato-propyl)-pyrrole-2,5-dione
5.0 g (27.3 mmol) of the compound that is prepared according to Example L4 is dissolved in 90 ml of tetrahydrofuran, mixed with 8 ml of triethylamine and 6.17 ml of phosphoric acid diphenylester azide, and it is stirred for 1.5 hours at 23 °C. Then, it is mixed with 110 ml of toluene, the tetrahydrofuran is distilled off, and it is heated for 2 hours to 70°C. The crude product is purified by chromatography on fine silica gel. 1.77 g (9.82 mmol, 36%) of the title compound is isolated.
Example L5 6-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-hexanoic acid
100 g (762 mmol) of 6-aminocaproic acid is reacted analogously to Example L5, and 93.8 g (444 mmol, 58%) of the title compound is isolated as a crystalline solid. iH-NMR (CDCI3): δ = 1.34 (2H), 1.55-1.70 (4H), 2.34 (2H), 3.51 (2H), 6.69 (2H) ppm.
Example L5a l-(5-Isocyanato-pentyl)-pyrrole-2,5-dione
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 L6
1 l-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic acid 10 g (49.7 mmol) of 11-aminoundecanoic acid is reacted analogously to Example L5, and 6.29 g (22.4 mmol, 45%) of the title compound is isolated as a crystalline solid.
1H-NMR (CDCI3): δ = 1.19-1.36 (12H), 1.51-1.67 (4H), 2.34 (2H), 3.49 (2H), 6.68 (2H) ppm.
Example L6a
1 -(10-Isocyanato-decyl)-pyrrole-2,5-dione
5.28 g (18.8 mmol) of the compound that is prepared according to Example L6 is reacted analogously to Example L4a, and 3.37 g (12.1 mmol, 64%) 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): δ = 6.28 (IH), 6.48 (IH), 6.53 (2H), 7.30 (2H), 7.50-
9.00 (2H) ppm.
Example L8 l-(4-Hydroxy-phenyl)-pyrrole-2,5-dione The suspension that consists of 5.0 g (45.8 mmol) of 4-aminophenol, 4.49 g of maleic acid anhydride and 40 ml of acetic acid is refluxed for 3 hours. It is concentrated by evaporation, residual acetic acid is removed azeotropically by repeated distillation with acetic acid, and the residue is purified by chromatography on fine silica gel. 2.83 g (15.0 mmol, 33%) of the title compound is isolated. iH-NMR (d6-DMSO): δ = 6.83 (2H), 7.09 (2H), 7.13 (2H), 9.71 (IH) ppm.
Example L9 4-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-butanoic acid 4-hydroxymethyl-2-nitro-phenyl ester
The solution of 5.0 g (29.6 mmol) of 4-hydroxymethyl-2-nitro-phenol in 250 ml of dichloromethane is mixed with 6.1 g of N,N'-dicyclohexylcarbodiimide and 2.4 ml of pyridine, and the solution of 5.5 g of the compound, prepared according to
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): δ = 2.07 (3H), 2.67 (2H), 3.67 (2H), 4.79 (2H), 6.72 (2H),
7.28 (IH), 7.66 (IH), 8.10 (IH) ppm.
Example L10
6-(2,5-Dioxo-2,5-dihydro-pyrrol- 1 -yl)-hexanoic acid 4-hydroxymethyl-2-nitro-phenyl ester
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
L5, and after working-up and purification, 3.78 g (10.4 mmol, 35%) of the title compound is isolated. iH-NMR (CDCI3): δ = 1.42 (2H), 1.66 (2H), 1.88 (2H), 2.64 (2H), 3.55 (2H),
4.78 (2H), 6.69 (2H), 7.21 (IH), 7.64 (IH), 8.09 (IH) ppm.
Example Ll 1
1 l-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic acid 4-hydroxymethyl-2-nitro- phenyl ester
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
L6, and after working-up and purification, 3.78 g (10.4 mmol, 35%) of the title compound is isolated. iH-NMR (CDCI3): δ = 1.21-1.63 (14H), 1.76 (2H), 1.99 (IH), 2.63 (2H), 3.51
(2H), 4.78 (2H), 6.68 (2H), 7.21 (IH), 7.65 (IH), 8.10 (IH) ppm.
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. The mixture is stirred for 16 hours at 23 °C, filtered, the filtrate is concentrated and purified by chromatography on fine silica gel. 7.18 g (17.8 mmol, 77%) 4-(2,5-Dioxo-2,5-dihydro- pyrrol-l-yl)-butanoic acid-4-tert-butyldimethylsilanyloxymethyl-phenyl ester are isolated. 1.42 g thereof are dissolved in 63 ml THF and 7 ml water, and 0.67g (3.52 mmol) p-toluenesulfonic acid are added at room temperature. After 16 hours, a saturated sodium bicarbonate solution is added and the mixture is extracted several times with ethyl acetate. The combined organic layers are washed with a saturated solution of sodium chloride, dried over sodium sulfate and purified by chromatography on fine silica gel. 0.43 g (1.5 mmol, 42%) of the title compound are isolated.
1H-NMR (CDC13): δ = 1.71 (IH), 2.04 (2H), 2.58 (2H), 3.67 (2H), 4.68 (2H), 6.71 (2H), 7.09 (2H), 7.38 (2H) ppm.
Example L13 6-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-hexanoic acid 4-hydroxymethyl-phenyl ester Analogously to Example L12, 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. After working-up, purification and analogous treatment with p-toluenesulfonic acid, 3,19 g (10.1 mmol, 60%) of the title compound are isolated.
1H-NMR (CDCI3): δ = 1.42 (2H), 1.59-1.83 (5H), 2.55 (2H), 3.55 (2H), 4.68 (2H), 6.69 (2H), 7.06 (2H), 7.38 (2H) ppm.
Example L14 1 l-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic acid 4-hydroxymethyl-phenyl ester
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.
1H-NMR (CDC13): δ = 1.24-1.43 (12H), 1.57 (3H), 1.74 (2H), 2.55 (2H), 3.50 (2H), 4.69 (2H), 6.68 (2H), 7.06 (2H), 7.38 (2H) ppm.
Example Ll 5
4-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-butanoic 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 5.42 g of the compound prepared according to Example L4. After working-up and purification, 8.49 g (26.2 mmol, 89%) of the title compound are isolated.
1H-NMR (CDCI3): δ = 2.07 (3H), 2.64 (2H), 3.67 (2H), 4.67 (2H), 6.72 (2H), 7.14 (IH), 7.27 (IH), 7.46 (IH) ppm.
Example L16
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.
1H-NMR (CDCI3): δ = 1.43 (2H), 1.66 (2H), 1.81 (3H), 2.61 (2H), 3.55 (2H), 4.67 (2H), 6.69 (2H), 7.10 (IH), 7.26 (IH), 7.46 (IH) ppm.
Example L17
1 l-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic acid 4-hydroxymethyl-2-chloro- phenyl ester Analogously to Example L9, 4.61 g (29 mmol) 4-hydroxymethyl-2-chloro-phenol are reacted with 8.17 g of the compound prepared according to Example L6. After working-up and purification, 4.61 g (10.9 mmol, 38%) of the title compound are isolated. 1H-NMR (CDCI3): δ= 1.18-1.84 (17H), 2.61 (2H), 3.51 (2H), 4.67 (2H), 6.68 (2H), 7.10 (IH), 7.27 (IH), 7.46 (IH) ppm.
Example Ll 8 1 -(6-Hydroxy-hexyl)-pyrrol-2,5-dione
26 ml of a 1,0M solution of borane-tetrahydrofurane-complex in tetrahydrofurane is added to a solution of 5.0 g (23.7 mmol) of the acid prepared according to Example L5 in 50 ml of anhydrous tetrahydrofurane and the mixture is stirred for 3 hours at 23°C. The mixture is poured into a saturated solution of sodium bicarbonate, extracted several times with ethyl acetate, and the combined organic extracts are dried over sodium sulfate. After filtration and removal of the solvent, the residue is purified by chromatography. 2.53 g (12.8 mmol, 54%) of the title compound are isolated. 1H-NMR (CDCI3): δ= 1.24-1.65 (9H), 3.52 (2H), 3.63 (2H), 6.68 (2H) ppm.
Examples of the Synthesis of Effector-Linker Conjugates (EL)
Example ELI
(4S,7R,8S,9S,13Z,16S)-[3-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-propyl]-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
Example EL la (4S,7R,8S,9S,13Z,16S)-7-Allyl-8-(tert-butyl-dimethyl-silanyloxy)-4-hydroxy- 5 ,5 ,9, 13 -tetramethyl- 16-(2-methyl-benzothiazol-5 -yl)-oxacyclohexadec- 13 -ene-2,6- dione
The solution of 6.0 g (7.93 mmol) of (4S,7R,8S,9S,13Z,16S)-7-allyl-4,8- bis(tert-butyl-dimefhyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5- yl)-oxacyclohexadec-13-ene-2,6-dione, which was produced analogously to the process that is described in WO 00/66589, in 186 ml of anhydrous dichloromethane is mixed at 0°C with 26.4 ml of a 20% solution of trifluoroacetic acid in dichloromethane, and it is stirred for 6 hours at 0°C. It is poured into saturated sodium bicarbonate solution, extracted with dichloromethane, the combined organic extracts are washed with water 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. 3.32 g (5.17 mmol, 65%) of the title compound is isolated as a colorless solid. iH-NMR (CDCI3): δ = 0.09 (3H), 0.12 (3H), 0.93 (9H), 1.00 (3H), 1.06 (3H), 1.22 (3H), 1.70 (3H), 1.03-1.77 (5H), 1.95 (IH), 2.31-2.56 (6H), 2.83 (3H), 2.87 (IH), 3.00 (IH), 3.30 (IH), 3.90 (IH), 4.09 (IH), 4.94-5.03 (2H), 5.20 (IH), 5.77 (IH), 5.88 (IH), 7.34 (IH), 7.78 (IH), 7.95 (IH) ppm.
Example EL lb
(4S,7R,8S,9S,13Z,16S)-3-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-propyl]-carbamic acid- 7-allyl-8-tert-butyl-dimethylsilyloxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol- 5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yl ester
50 mg (78 μmol) 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 μmol, 80%) of the title compound is isolated as a colorless oil.
Example ELI
(4S,7R,8S,9S,13Z,16S)-[3-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-ρropyl]-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
The solution of 41 mg (50 μmol) of the compound, prepared according to Example lb, in a mixture of 0.8 ml of tetrahydrofuran and 0.8 ml of acetonitrile is mixed with 310 μl of hexafluorosilicic acid, 310 μl of hydrogen fluoride-pyridine complex, and it is stirred for 23 hours at 23 °C. It is poured into a 5% sodium hydroxide solution, extracted with ethyl acetate, the combined organic extracts are washed with a 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 thin-layer plates, and 26 mg (36.7 μmol, 73%) of the title compound is isolated as a colorless foam. H-NMR (CDC13): δ = 0.99 (3H), 1.14 (3H), 1.17 (3H), 1.20-1.51 (3H), 1.54- 1.87 (6H), 1.70 (3H), 2.22 (IH), 2.28-3.02 (9H), 2.83 (3H), 3.31 (IH), 3.45 (IH), 3.68 (IH), 4.44+4.83 (IH), 4.99 (IH), 5.03 (IH), 5.15 (IH), 5.61 (IH), 5.72 (IH), 5.91 (IH), 6.68 (2H), 7.36 (IH), 7.78 (IH), 7.90 (IH) ppm.
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-dioxabicyclo[14.1.0]heptadec-7-yl ester (B) The solution of 44 mg (62.2 μmol) of the compound, prepared according to
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 μmol, 50%) of title compound A as well as 7.6 mg (10.5 μmol, 17%) of title compound B are isolated in each case as a colorless foam. iH-NMR (CDC13) of A: δ = 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: δ = 1.02 (6H), 1.26 (3H), 1.33 (IH), 1.23-2.27 (12H),
2.54-2.78 (4H), 2.82 (3H), 2.91 (IH), 3.13 (IH), 3.40 (2H), 3.66 (IH), 4.11 (IH), 4.84 (IH), 4.95 (IH), 5.01 (IH), 5.70 (IH), 5.81+5.93 (IH), 6.04+6.13 (IH), 6.69 (2H), 7.35 (IH), 7.75 (IH), 7.90+7.99 (IH) ppm.
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
Example EL3a
(4S,7R,8S,9S, 13Z, 16S)-[5-(2,5-Dioxo-2,5-dihydro-pyrrol-l -yl)-pentyl]-carbamic acid-
7-allyl-8-tert-butyl-dimethylsilyloxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-
5-yl)-2,6-dioxo-oxacyclohexadec- 13 -en-4-yl ester
50 mg (78 μmol) 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 μmol, 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 μmol) of the compound that is prepared according to Example EL3a is reacted analogously to Example ELI, and after purification, 43 mg (58.4 μmol, 59%) of the title compound is isolated as a colorless foam. iH-NMR (CDC13): δ = 0.89 (3H), 0.96 (3H), 0.85-1.97 (17H), 1.12 (3H), 2.16- 3.01 (10H), 2.82 (3H), 3.44 (IH), 3.65 (IH), 4.41+4.53 (IH), 4.98 (IH), 5.03 (IH), 5.15 (IH), 5.60 (IH), 5.71 (IH), 5.90 (IH), 6.68 (2H), 7.35 (IH), 7.77 (IH), 7.89+7.96 (IH) ppm.
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
(lR,3S,7S,10R,llS,12S,16S)-[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 (B)
26 mg (35.3 μmol) of the compound that is prepared according to Example EL3 is reacted analogously to Example EL2, and after purification, 9.1 mg (12.1 μmol,
34%) of title compound A as well as 3.0 mg (4.0 μmol, 11%) of title compound B are isolated in each case as a colorless foam. iH-NMR (CDCI3) of A: δ = 0.83-1.94 (15H), 0.98 (3H), 1.14 (3H), 1.16 (3H),
1.32 (3H), 2.15-2.82 (8H), 2.84 (3H), 3.44 (2H), 3.51 (IH), 3.66 (IH), 4.46 (IH), 4.99
(IH), 5.04 (IH), 5.54 (IH), 5.69 (IH), 6.06 (IH), 6.68 (2H), 7.33 (IH), 7.80 (IH), 7.89
(IH) ppm.
1H-NMR (CDCI3) of B: δ = 0.78-2.74 (23H), 1.01 (3H), 1.03 (3H), 1.33 (3H), 2.82 (3H), 2.91 (IH), 3.14 (IH), 3.39 (IH), 3.47 (2H), 3.67 (IH), 4.12 (IH), 4.49 (IH),
4.92-5.06 (2H), 5.53+5.80 (IH), 5.69 (IH), 6.11 (IH), 6.68 (2H), 7.34 (IH), 7.74+7.79
(IH), 7.89+8.02 (IH) ppm.
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 Example EL5a
(4S,7R,8S,9S, 13Z, 16S)-[10-(2,5-Dioxo-2,5-dihydro-pyrrol-l -yl)-decyl] -carbamic acid-7-allyl-8-tert-butyl-dimethylsilyloxy-5 ,5 ,9, 13 -tetramethyl- 16-(2-methyl- benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec- 13 -en-4-yl ester 50 mg (78 μmol) of the compound that is prepared according to Example ELI a is reacted analogously to Example ELlb with the linker that is produced according to Example L6a, and after purification, 56 mg (60.8 μmol, 78%) of the title compound is isolated as a colorless oil.
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
20 mg (21.7 μmol) of the compound that is prepared according to Example EL5a is reacted analogously to Example ELI , and after purification, 10 mg (12.4 μmol, 57%) of the title compound is isolated as a colorless foam. lH-NMR (CDCl3): δ - 0.91-1.87 (22H), 0.97 (3H), 1.13 (3H), 1.17 (3H), 1.70 (3H), 2.18-2.69 (8H), 2.80 (IH), 2.82 (3H), 2.96 (IH), 3.47 (IH), 3.50 (2H), 3.66 (IH), 3.97+4.36 (IH), 4.98 (IH), 5.04 (IH), 5.16 (IH), 5.61 (IH), 5.72 (IH), 5.91 (IH), 6.68 (2H), 7.37 (IH), 7.77 (IH), 7.90+7.97 (IH) ppm.
Example EL6
(lS,3S,7S,10R,HS,12S,16R)-[10-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-decyl]- 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
(lR,3S,7S,10R,HS,12S,16S)-[10-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-decyl]- carbamic acid- 10-allyl- 11 -hydroxy-8,8, 12, 16-tetramethyl-3-(2-methyl-benzothiazol-5- yl)-5,9-dioxo-4,17-dioxabicyclo[14!.0]heptadec-7-yl ester (B)
18 mg (22 μmol) of the compound that is prepared according to Example EL5 is reacted analogously to Example EL2, and after purification, 9.2 mg (11.2 μmol,
51%) of title compound A as well as 3.2 mg (3.9 μmol, 18%) of title compound B are isolated in each case as a colorless foam. iH-NMR (CDCI3) of A: δ = 0.98 (3H), 1.14 (3H), 1.16 (3H), 1.32 (3H), 1.03- 1.67 (21H), 1.71-1.94 (3H), 2.18-2.78 (9H), 2.83 (3H), 3.50 (3H), 3.66 (IH), 3.87+4.43 (IH), 4.98 (IH), 5.04 (IH), 5.53 (IH), 5.69 (IH), 6.07 (IH), 6.68 (2H), 7.33 (IH), 7.80 (IH), 7.89+7.93 (IH) ppm. iH-NMR (CDCI3) of B: δ = 0.80-1.64 (21H), 1.01 (3H), 1.03 (3H), 1.25 (3H), 1.33 (3H), 1.79-2.25 (5H), 2.34+3.14 (IH), 2.52-2.76 (4H), 2.81 (3H), 2.91 (IH), 3.40 (IH), 3.51 (2H), 3.67+3.82 (IH), 4.13+4.26 (IH), 4.46 (IH), 4.94 (IH), 5.01 (IH), 5.70 (IH), 5.81+5.94 (IH), 6.05+6.12 (IH), 6.68 (2H), 7.36 (IH), 7.74 (IH), 7.91+8.02 (IH) ppm.
Example EL7
(4S,7R,8S,9S,13Z,16S)-[3-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-propyl]-carbamic acid- 7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo- oxacyclohexadec- 13 -en- 8-yl ester
Example EL7a
(4S,7R,8S,9S,13Z,16S)-7-Allyl-4-(tert-butyl-dimethyl-silanyloxy)-8-hydroxy- 5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6- dione The solution of 5.3 g (7.01 mmol) of (4S,7R,8S,9S,13Z,16S)-7-allyl-4,8- bis(tert-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5- yl)-oxacyclohexadec-13-ene-2,6-dione, which was produced analogously to the process described in WO 00/66589, in a mixture of 85 ml of tetrahydrofuran and 85 ml of acetonitrile, is mixed with 31.7 ml of hexafluorosilicic acid, cooled to 0°C, 8.1 ml of trifluoroacetic acid is added dropwise, and it is stirred for 20 hours at 0°C. It is poured into water, neutralized by adding a saturated sodium bicarbonate solution and extracted several times with ethyl acetate. The combined organic extracts are washed with saturated sodium chloride solution, dried over sodium sulfate, and the residue that is obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel. 2.82 g (4.39 mmol, 63%) of the title compound is isolated as a colorless solid. iH-NMR (CDCI3): δ = -0.09 (3H), 0.08 (3H), 0.84 (9H), 1.08 (3H), 1.10 (3H), 1.12 (3H), 1.21-1.86 (5H), 1.70 (3H), 2.15 (IH), 2.29-2.97 (8H), 2.84 (3H), 3.14 (IH), 3.96 (IH), 4.03 (IH), 4.97-5.06 (2H), 5.23 (IH), 5.61 (IH), 5.77 (IH), 7.35 (IH), 7.79 (IH), 7.93 (IH) ppm.
Example EL7b (4S,7R,8S,9S,13Z,16S)-[3-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-propyl]-carbamic acid-
7-allyl-4-tert-butyl-dimethylsilyloxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-
5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yl ester
100 mg (156 μmol) of the compound that is prepared according to Example
EL7a is reacted analogously to Example ELlb with the linker that is produced according to Example L4a, and after purification, 121 mg (147 μmol, 94%) of the title compound is isolated as a colorless oil.
Example EL7
(4S,7R,8S,9S, 13Z, 16S)-[3-(2,5-Dioxo-2,5-dihydro-pyrrol-l -yl)-propyl]-carbamic acid- 7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo- oxacyclohexadec-13-en-8-yl ester
46 mg (56 μmol) of the compound that is prepared according to Example EL7b is reacted analogously to Example ELI, and after purification, 17 mg (24 μmol, 43%) of the title compound is isolated as a colorless foam. H-NMR (CDC13): δ = 0.99-1.30 (2H), 1.03 (3H), 1.07 (3H), 1.21 (3H), 1.51-
1.97 (6H), 1.72 (3H), 2.27-2.61 (6H), 2.83 (3H), 2.88 (IH), 3.09 (IH), 3.14 (2H), 3.51
(IH), 3.58 (2H), 4.04 (IH), 4.96-5.04 (2H), 5.12 (IH), 5.19 (IH), 5.28 (IH), 5.75 (IH),
5.86 (IH), 6.66 (2H), 7.35 (IH), 7.78 (IH), 7.96 (IH) ppm.
Example EL8
(lS,3S,7S,10R,HS,12S,16R)-[3-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-propyl]- carbamic acid-10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5- yl)-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-ll-yl ester (A) and (lS,3S,7S,10R,HS,12S,16R)-[3-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-propyl]- carbamic acid- 10-allyl-7-hydroxy-8,8, 12, 16-tetramethyl-3 -(2-methyl-benzothiazol-5- yl)-5,9-dioxo-4,17-dioxabicyclo[14.1.0]-heptadec-l 1-yl ester (B) 29 mg (41 μmol) of the compound that is prepared according to Example EL7 is reacted analogously to Example EL2, and after purification, 18 mg (24.9 μmol, 61%) of title compound A as well as 3.0 mg (4.1 μmol, 10%) of title compound B are isolated in each case as a colorless foam. iH-NMR (CDCI3) of A: δ = 0.98 (3H), 1.05 (3H), 1.24 (3H), 1.26 (3H), 1.12-
1.83 (9H), 2.12-2.46 (4H), 2.59 (2H), 2.76 (IH), 2.84 (3H), 3.14 (2H), 3.59 (3H), 3.98 (IH), 4.10 (IH), 4.95-5.02 (2H), 5.17 (2H), 5.77 (IH), 6.19 (IH), 6.70 (2H), 7.38 (IH), 7.82 (IH), 7.97 (IH) ppm. iH-NMR (CDCI3) of B: δ = 0.96 (3H), 1.01 (3H), 1.13-1.86 (11H), 1.28 (3H), 1.32 (IH), 2.16-2.50 (6H), 2.84 (3H), 3.02 (IH), 3.15 (2H), 3.50 (IH), 3.61 (2H), 3.88 (IH), 4.19 (IH), 4.96-5.04 (2H), 5.13 (IH), 5.28 (IH), 5.78 (IH), 6.33 (IH), 6.71 (2H), 7.36 (IH), 7.81 (IH), 7.96 (IH) ppm.
Example EL9 (4S,7R,8S,9S,13Z,16S)-[5-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-pentyl]-carbamic acid- 7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo- oxacyclohexadec-13-en-8-yl ester
Example EL9a (4S,7R,8S,9S,13Z,16S)-[5-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-pentyl]-carbamic acid-
7-allyl-4-tert-butyl-dimethylsilyloxy-5 ,5 ,9, 13 -tetramethyl- 16-(2-methyl-benzothiazol-
5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yl ester
100 mg (156 μmol) of the compound that is prepared according to Example
EL7a is reacted analogously to Example ELlb with the linker that is produced according to Example L5a, and after purification, (65.9 μmol, 42%) of the title compound is isolated as a colorless oil.
Example EL9
(4S,7R,8S,9S,13Z,16S)-[5-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-pentyl]-carbamic acid-
7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo- oxacyclohexadec-13-en-8-yl ester
56 mg (65.9 μmol) of the compound that is prepared according to Example
EL7b is reacted analogously to Example ELI, and after purification, 24.7 mg (33.6 μmol, 51%) of the title compound is isolated as a colorless foam. iH-NMR (CDCI3): δ = 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
(lS,3S,7S,10R,llS,12S,16R)-[5-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-pentyl]-carbamic acid- 10-allyl-7-hydroxy-8,8, 12, 16-tetramethyl-3 -(2-methyl-benzothiazol-5-yl)-5,9- dioxo-4,17-dioxabicyclo[14.1.0]heptadec-ll-yl ester (A) and (lS,3S,7S,10R,llS,12S,16R)-[5-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-ρentyl]-carbamic acid-10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9- dioxo-4,17-dioxabicyclo[14.1.0]hepta-dec-ll-yl ester (B)
24.7 mg (33.6 μmol) of the compound that is prepared according to Example EL9 is reacted analogously to Example EL2, and after purification, 16.7 mg (22.2 μmol, 66%) of title compound A as well as 2.0 mg (2.7 μmol, 8%) of title compound B are isolated in each case as a colorless foam. iH-NMR (CDCI3) of A: δ = 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: δ = 0.83-1.85 (13H), 0.95 (3H), 1.01 (3H), 1.27 (3H),
1.32 (3H), 2.17-2.49 (6H), 2.84 (3H), 3.03 (IH), 3.17 (2H), 3.48 (IH), 3.53 (2H), 3.86 (IH), 4.18 (IH), 4.66 (IH), 4.94-5.03 (2H), 5.27 (IH), 5.76 (IH), 6.33 (IH), 6.69 (2H), 7.35 (IH), 7.81 (IH), 7.96 (IH) ppm. Example ELI 1 (lS,3S(E),7S,10R,HS,12S,16R)-[3-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-propyl]- carbamic acid 7-[3-(2,5-dioxo-2,5-dihydro-pyrrol-l -yl)-propylcarbamoyloxy]- 8,8, 10,12, 16-pentamethyl-3-[l -methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-5,9-dioxo- 4,17-dioxa-bicyclo[14.1.0]heptadec-l 1-yl ester
10 mg (19.7 μmol) of (lS,3S(E),7S,10R,HS,12S,16R)-7,ll-dihydroxy- 8,8,10,12,16-pentamethyl-3-[l-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-5,9-dioxo- 4,17-dioxa-bicyclo[14.1.0]heptadecane is reacted analogously to Example ELlb with the linker that is produced according to Example L4a, and after purification, 7 mg (8.06 μmol, 41%) of the title compound is isolated as a colorless oil. iH-NMR (CDCI3): δ = 0.88-2.20 (13H), 1.03 (3H), 1.05 (3H), 1.10 (3H), 1.24 (3H), 1.28 (3H), 2.08 (3H), 2.63-2.85 (4H), 2.71 (3H), 2.99-3.25 (3H), 3.41-3.50 (3H), 3.62 (2H), 4.88-5.70 (5H), 6.52 (IH), 6.69 (2H), 6.71 (2H), 7.02 (IH) ppm.
Example EL 12
(4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2- methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-l 3-en-4-yl ester 4-(2,5-dioxo- 2,5-dihydro-pyrrol-l-yl)-phenyl ester
Example ELI 2a
(4S,7R,8S,9S,13Z,16S)-Chloroformic 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
The solution of 1.0 g (1.56 mmol) of the compound, prepared according to Example ELI a, in 20 ml of dichloromethane is mixed at 0°C with the solution of 285 mg of triphosgene in 6 ml of dichloromethane, 160 μl of pyridine, and it is stirred for 2.5 hours at 23°C. It is concentrated by evaporation, the residue is dissolved in ethyl acetate, washed with water and 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. 1.08 g (1.53 mmol, 98%) of the title compound is isolated.
Example ELI 2b
(4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-8-(tert-butyl-dimethyl-silanyloxy)- 5,5,9,13-tetramethyl-l 6-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-l 3- en-4-yl ester 4-(2,5-dioxo-2,5-dihydro-pyrrol-l-yl)-phenyl ester
The solution of 267 mg (370 μmol) of the compound, prepared according to
Example ELI 2a, in 16 ml of ethyl acetate, is mixed with 51 μl 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 μmol, 59%) of the title compound is isolated.
Example ELI 2 (4S,7R,8S,9S,13Z,16S)-Carbonic 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 4-(2,5-dioxo-
2,5-dihydro-pyrrol- 1 -yl)-phenyl ester
Analogously to Example ELI, 248 mg (289 μmol) of the compound that is prepared according to Example EL 12a is reacted, and after working-up and purification, 149 mg (201 μmol, 69%) of the title compound is isolated.
1H-NMR (CDCI3): δ = 1.08 (3H), 1.14 (3H), 1.26 (3H), 1.04-1.90 (8H), 2.24-
2.57 (6H), 2.68-2.99 (3H), 2.81 (3H), 3.45 (IH), 3.72 (IH), 5.02 (IH), 5.06 (IH), 5.17
(IH), 5.65 (IH), 5.74 (IH), 5.98 (IH), 6.79 (2H), 6.88 (2H), 7.21 (2H), 7.33 (IH), 7.64
(IH), 7.97 (IH) ppm.
Example EL 13
(lS,3S,7S,10R,llS,12S,16R)-Carbonic acid-10-allyl-l l-hydroxy-8,8,12,16- tetramethyl-3 -(2-methyl-benzothiazol-5 -yl)-5 ,9-dioxo-4, 17-dioxa- bicyclo[14!.0]heptadec-7-yl ester 4-(2,5-dioxo-2,5-dihydro-pyrrol-l-yl)-phenyl ester Analogously to Example EL2, 144 mg (194 μmol) of the compound that is prepared according to Example EL 12 is reacted, and after working-up and purification,
89 mg (117 μmol, 60%) of the title compound is isolated. iH-NMR ^DC^): δ = 1.10 (3H), 1.14 (3H), 1.27 (3H), 1.32 (3H), 1.19-1.85
(7H), 2.08-2.89 (8H), 2.81 (3H), 3.50 (IH), 3.70 (IH), 5.02 (IH), 5.07 (IH), 5.58 (IH), 5.72 (IH), 6.10 (IH), 6.81 (2H), 6.88 (2H), 7.21 (2H), 7.31 (IH), 7.68 (IH), 7.93 (IH) ppm.
Example EL 14
(4S,7R,8S,9S, 13Z, 16S)-Carbonic acid 7-allyl-4-hydroxy-5,5,9, 13 -tetramethyl- 16-(2- methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yl ester 4-(2,5-dioxo- 2,5-dihydro-pyrrol- 1 -yl)-phenyl ester
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
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 14b
(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-(2,5-dioxo-2,5-dihydro-pyrrol-l-yl)-phenyl ester
The solution of 313 mg (0.44 mmol) of the compound, prepared according to
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 μl 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 μmol, 79%) of the title compound is isolated.
Example EL 14
(4S,7R,8S,9S,13Z, 16S)-Carbonic acid 7-allyl-4-hydroxy-5,5,9, 13 -tetramethyl- 16-(2- methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-l 3-en-8-yl ester 4-(2,5-dioxo-
2,5-dihydro-pyrrol-l -yl)-phenyl ester Analogously to Example ELI, 304 mg (355 μmol) of the compound that is prepared according to Example EL 14a is reacted, and after working-up and purification, 67 mg (90 μmol, 25%) of the title compound is isolated. lH-NMR (CDCl3): δ = 1.09 (3H), 1.11 (3H), 0.84-2.02 (7H), 1.27 (3H), 1.72
(3H), 2.29-2.58 (6H), 2.84 (3H), 2.89 (IH), 2.96 (IH), 3.63 (IH), 4.03 (IH), 5.06 (2H), 5.23 (2H), 5.80 (IH), 5.85 (IH), 6.86 (2H), 7.30 (2H), 7.35 (IH), 7.39 (IH), 7.80 (IH),
7.96 (IH) ppm.
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
Analogously to Example EL2, 67 mg (90 μmol) of the compound that is prepared according to Example EL 14 is reacted, and after working-up and purification, 32 mg (42 μmol, 47%) of the title compound is isolated.
1H-NMR (CDC13): δ = 1.05 (3H), 1.06 (3H), 1.25 (3H), 1.35 (3H), 1.21-1.90 (7H), 2.18 (2H), 2.33-2.67 (4H), 2.73 (IH), 2.85 (3H), 3.79 (IH), 4.11 (IH), 4.33 (IH), 5.02 (IH), 5.07 (IH), 5.31 (IH), 5.81 (IH), 6.27 (IH), 6.86 (2H), 7.29 (2H), 7.35-7.41 (3H), 7.83 (IH), 7.99 (IH) ppm.
Example EL 16
(lS,3S(E),7S,10R,HS,12S,16R)-N-[l-({4-[2-(7,l l-Dihydroxy-8,8,10,12,16- pentamethyl-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-3-yl)-propenyl]-thiazol-2- ylmethyl}-carbamoyl)-ethyl]-3-methyltrisulfanyl-N-methyl-propionamide
The solution of 7 mg (13 μmol) of (lS,3S(E),7S,10R,HS,12S,16R)-3-[2-(2- aminomethyl-thiazol-4-yl)- 1 -methyl- vinyl]-7, 11 -dihydroxy-8,8, 10,12,16-penta- methyl-4,17-dioxa-bicyclo[14!.0]heptadecane-5,9-dione, which was produced analogously to the process described in WO 99/01124, in 0.5 ml of dichloromethane is mixed with 7 mg of the compound that is prepared according to Example Ll, 0.4 mg of 4-dimethylaminopyridine and 4 mg of Ν,Ν'-dicyclohexylcarbodiimide are added, and it is stirred for 20 minutes at 23 °C. Precipitated urea is filtered out, and it is purified by chromatography on a preparative thin-layer plate. 5 mg (6.5 μmol, 50%) of the title compound is isolated. 1H-NMR (CDCI3): δ = 1.00 (3H), 1.08 (3H), 1.17 (3H), 1.23-1.77 (5H), 1.28
(3H), 1.36 (3H), 1.39 (3H), 1.88-2.13 (3H), 2.10 (3H), 2.37 (IH), 2.49-2.66 (2H), 2.55 (3H), 2.77-2.92 (4H), 2.97 (3H), 3.16 (2H), 3.31 (IH), 3.77 (IH), 4.08 (IH), 4.19 (IH), 4.62 (IH), 4.76 (IH), 5.25 (IH), 5.45 (IH), 6.57 (IH), 7.01 (IH), 7.06 (IH) ppm.
Example EL 17
(lS,3S(E),7S,10R,llS,12S,16R)-2-[Methyl-(3-methyltrisulfanyl-propionyl)-amino]- propionic acid-4-[2-(7, 11 -dihydroxy-8,8,10, 12, 16-pentamethyl-5,9-dioxo-4,l 7-dioxa- bicyclo[l 4.1.0]heptadec-3-yl)-propenyl]-thiazol-2-ylmethyl ester Analogously to Example EL16, 10 mg (19 μmol) of (1S,3S(E),7S,10R,11S, 12S, 16R)-7, 11 -dihydroxy-3 -[2-(2-hydroxymethyl-thiazol-4-yl)- 1 -methyl-vinyl]- 8,8, 10, 12, 16-pentamethyl-4, 17-dioxa-bicyclo [ 14.1.0] heptadecane-5,9-dione, which was produced analogously to the process that is described in WO 99/01124, is reacted, and 2.2 mg (2.8 μmol, 15%) of the title compound is isolated. iH-NMR (CDC13): δ = 1.01 (3H), 1.09 (3H), 1.18 (3H), 1.27 (IH), 1.28 (3H), 1.32-1.76 (3H), 1.37 (3H), 1.47 (3H), 1.95 (IH), 2.06 (IH), 2.12 (3H), 2.38 (IH), 2.51- 2.63 (2H), 2.56 (3H), 2.78-2.92 (5H), 2.97+3.01 (3H), 3.13-3.35 (3H), 3.71 (IH), 3.77 (IH), 4.00 (IH), 4.18 (IH), 5.25 (IH), 5.39 (2H), 5.45 (IH), 6.60 (IH), 7.17 (IH) ppm.
Example EL 18
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]-2-nitro-phenyl ester
Example ELI 8a
4-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-butanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[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-yloxycarbonyloxymethyl]-2- nitro-phenyl ester
Analogously to Example EL 12b, 200 mg (284 μmol) 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 μmol, 45%) of the title compound is isolated.
Example EL 18
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]-2 -nitro-phenyl ester Analogously to Example ELI , 129 mg (129 μmol) of the compound that is prepared according to Example ELI 8a is reacted, and after working-up and purification, 71 mg (80 μmol, 62%) of the title compound is isolated. H-NMR (CDCI3): δ = 0.88-2.11 (11H), 1.02 (3H), 1.14 (3H), 1.71 (3H), 2.23- 2.56 (6H), 2.63-2.71 (3H), 2.74 (3H), 2.97 (IH), 3.39 (IH), 3.68 (3H), 4.58 (IH), 4.78 (IH), 5.01 (IH), 5.05 (IH), 5.18 (IH), 5.56 (IH), 5.71 (IH), 5.97 (IH), 6.73 (2H), 7.19 (IH), 7.31 (IH), 7.36 (IH), 7.75 (IH), 7.77 (IH), 7.95 (IH) ppm.
Example EL 19
4-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-butanoic acid 4-(lS,3S,7S,10R,l 1S,12S,16R)- [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-7-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-ll-hydroxy-8,8,12,16-tetramethyl-3-(2- methyl-benzotl iazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-7- yloxycarbonyloxymethyl]-2-nitro-phenyl ester (B)
Analogously to Example EL2, 71 mg (80 μmol) of the compound that is prepared according to Example ELI 8 is reacted, and after working-up and purification, 41 mg (45 μmol, 57%) of title compound A as well as 12 mg (13 μmol, 17%) of title compound B are isolated.
1H-NMR (CDCI3) of A: δ = 1.04 (3H), 1.14 (3H), 1.16 (3H), 1.32 (3H), 1.34- 1.84 (6H), 2.01-2.74 (12H), 2.78 (3H), 2.86 (IH), 3.44 (IH), 3.68 (3H), 4.56 (IH), 4.74 (IH), 5.01 (IH), 5.06 (IH), 5.47 (IH), 5.70 (IH), 6.07 (IH), 6.73 (2H), 7.20 (IH), 7.32 (IH), 7.36 (IH), 7.77 (IH), 7.81 (IH), 7.90 (IH) ppm.
Example EL20
6-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-hexanoic aci 4-(4S,7R,8S,9S,13Z,16S)-[7- allyl-8-hydroxy-5,5,9,l 3-tetramethyl-l 6-(2-methyl-benzothiazol-5-yl)-2,6-dioxo- oxacyclohexadec-13-en-4-yloxycarbonyloxymethyl]-2 -nitro-phenyl ester
Example EL20a
6-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-hexanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[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-yloxycarbonyloxymethyl]-2- nitro-phenyl ester Analogously to Example EL12b, 243 mg (345 μmol) of the compound that is prepared according to Example ELI 2a is reacted with 1 g of the compound that is prepared according to Example L10, and after working-up and purification, 25 mg (24 μmol, 7%) of the title compound is isolated.
Example EL20
6-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-hexanoic 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] -2-nitro-phenyl ester Analogously to Example ELI, 212 mg (206 μmol) of the compound that is prepared according to Example EL20a is reacted, and after working-up and purification, 117 mg (128 μmol, 62%) of the title compound is isolated. iH-NMR (CDCI3): δ = 1.01 (3H), 1.14 (6H), 1.04-2.78 (20H), 1.70 (3H), 2.74 (3H), 2.97 (IH), 3.39 (IH), 3.56 (2H), 3.68 (IH), 4.11 (IH), 4.58 (IH), 4.77 (IH), 5.00 (IH), 5.05 (IH), 5.18 (IH), 5.56 (IH), 5.71 (IH), 5.97 (IH), 6.69 (2H), 7.12 (IH), 7.29 (IH), 7.36 (IH), 7.75 (2H), 7.94 (IH) ppm.
Example EL21
6-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-hexanoic acid 4-(lS,3S,7S,10R,l 1S,12S,16R)- [l0-allyl-l l-hydroxy-8,8,l2,l6-te1xamemyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo- 4,17-dioxa-bicyclo[14.1.0]heptadec-7-yloxycarbonyloxymethyl]-2-nitro-phenyl ester (A) and 6-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-hexanoic acid 4- (lR,3S,7S,10R,llS,12S,16S)-[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-nitro-phenyl ester (B)
Analogously to Example EL2, 117 mg (128 μmol) of the compound that is prepared according to Example EL20 is reacted, and after working-up and purification, 63 mg (68 μmol, 53%) of title compound A as well as 19 mg (20 μmol, 16%) of title compound B are isolated. 1H-NMR (CDCI3) of A: δ = 1.03 (3H), 1.14 (3H), 1.15 (3H), 1.32 (3H), 1.07-
2.75 (22H), 2.77 (3H), 2.86 (IH), 3.44 (IH), 3.55 (2H), 3.69 (IH), 4.55 (IH), 4.77 (IH), 5.01 (IH), 5.06 (IH), 5.47 (IH), 5.70 (IH), 6.08 (IH), 6.70 (2H), 7.14 (IH), 7.31 (IH), 7.35 (IH), 7.76 (IH), 7.80 (IH), 7.90 (IH) ppm. Example EL22
1 l-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic 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]-2 -nitro-phenyl ester
Example EL22a
1 l-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[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-yloxycarbonyloxymethyl]-2- nitro-phenyl ester
Analogously to Example EL12b, 243 mg (345 μmol) 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 μmol, 45%) of the title compound is isolated.
Example EL22
1 l-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic 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]-2-nitro-phenyl ester
Analogously to Example ELI, 171 mg (155 μmol) of the compound that is prepared according to Example EL22a is reacted, and after working-up and purification, 108 mg (110 μmol, 71%) of the title compound is isolated. iH-NMR (CDC13): δ = 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 EL23 1 l-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic acid 4-
(lS,3S,7S,10R,llS,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-nitro-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-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa- bicyclo[14.1.0]heptadec-7-yloxycarbonyloxymethyl]-2-nitro-phenyl ester (B)
Analogously to Example EL2, 108 mg (110 μmol) of the compound that is prepared according to Example EL22 is reacted, and after working-up and purification,
65.9 mg (65.8 μmol, 60%) of title compound A as well as 19.8 mg (20 μmol, 18%) of title compound B are isolated. iH-NMR (CDC13) of A: δ = 1.04 (3H), 1.14 (3H), 1.15 (3H), 1.63 (3H), 0.92-
1.85 (23H), 2.10-2.81 (9H), 2.77 (3H), 2.86 (IH), 3.45 (IH), 3.51 (2H), 3.69 (IH), 4.55 (IH), 4.74 (IH), 5.01 (IH), 5.06 (IH), 5.47 (IH), 5.70 (IH), 6.08 (IH), 6.68 (2H),
7.13 (IH), 7.31 (IH), 7.35 (IH), 7.77 (IH), 7.80 (IH), 7.90 (IH) ppm.
Example EL24
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-l 6-(2-methyl-benzothiazol-5-yl)-2,6-dioxo- oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-2-nitro-phenyl ester
Example EL24a
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]-2- nitro-phenyl ester
Analogously to Example EL 12b, 271 mg (385 μmol) 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
(193 μmol, 50%) of the title compound is isolated.
Example EL24
4-(2,5-Dioxo-2,5-dihydro-pyrrol- 1 -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]-2-nitro-phenyl ester Analogously to Example ELI, 193 mg (193 μmol) of the compound that is prepared according to Example EL24a is reacted, and after working-up and purification, 107 mg (120 μmol, 62%) of the title compound is isolated. iH-NMR (CDC13): δ = 1.02 (3H), 1.07 (3H), 1.23 (3H), 0.97-2.13 (8H), 1.71 (3H), 2.28-2.54 (6H), 2.67 (2H), 2.84 (3H), 2.88 (IH), 2.95 (IH), 3.56 (IH), 3.67 (2H), 4.01 (IH), 4.93 (IH), 4.98 (IH), 5.17 (IH), 5.22 (3H), 5.70 (IH), 5.84 (IH), 6.72 (2H), 7.30 (IH), 7.34 (IH), 7.69 (IH), 7.80 (IH), 7.95 (IH), 8.13 (IH) ppm.
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-dioxo-4, 17-dioxa-bicyclo [ 14.1.0]heptadec- 11- yloxycarbonyloxymethyl]-2-nitro-phenyl ester (B)
Analogously to Example EL2, 102 mg (115 μmol) of the compound that is prepared according to Example ELI 9 is reacted, and after working-up and purification, 65 mg (72 μmol, 63%) of title compound A as well as 3 mg (3.3 μmol, 3%) of title compound B are isolated.
1H-NMR (CDCI3) of A: δ = 0.97 (3H), 1.04 (3H), 1.23 (3H), 1.31 (3H), 1.10- 2.75 (18H), 2.85 (3H), 3.68 (2H), 3.71 (IH), 4.09 (IH), 4.28 (IH), 4.92 (IH), 4.97 (IH), 5.20 (2H), 5.23 (IH), 5.72 (IH), 6.26 (IH), 6.72 (2H), 7.30 (IH), 7.37 (IH), 7.68 (IH), 7.83 (IH), 7.98 (IH), 8.13 (IH) ppm.
Example EL26
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]-2 -nitro-phenyl ester
Example EL26a
6-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-hexanoic 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] -2- nitro-phenyl ester
Analogously to Example EL 12b, 273 mg (387 μmol) 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 μmol, 17%) of the title compound is isolated.
Example EL26
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]-2 -nitro-phenyl ester
Analogously to Example ELI, 69 mg (67 μmol) of the compound that is prepared according to Example EL26a is reacted, and after working-up and purification, 26 mg (28 μmol, 42%) of the title compound is isolated. 1H-NMR (CDC13): δ = 0.93 (3H), 0.95 (3H), 1.16 (3H), 1.60 (3H), 0.98-2.61
(20H), 2.73 (3H), 2.77 (IH), 3.45 (3H), 3.83 (IH), 4.05 (IH), 4.83 (IH), 4.88 (IH),
5.05 (IH), 5.13 (3H), 5.62 (IH), 5.74 (IH), 6.61 (2H), 7.16 (IH), 7.26 (IH), 7.60 (IH),
7.70 (IH), 7.88 (IH), 8.03 (IH) ppm.
Example EL27
6-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-hexanoic acid 4-(lS,3S,7S,10R,llS,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- 11 -yloxycarbonyloxymethyl] -2-nitro-phenyl ester (A) and 6-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-hexanoic acid 4- (lR,3S,7S,10R,l lS,12S,16S)-[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- 11 - yloxycarbonyloxymethyl]-2-nitro-phenyl ester (B)
Analogously to Example EL2, 38 mg (41 μmol) of the compound that is prepared according to Example EL 19 is reacted, and after working-up and purification, 14 mg (15 μmol, 37%) of title compound A as well as 2 mg (2 μmol, 5%) of title compound B are isolated.
1H-NMR (CDCI3) of A: δ = 0.96 (3H), 1.03 (3H), 1.08-1.86 (13H), 1.23 (3H), 1.30 (3H), 2.16 (2H), 2.23-2.78 (7H), 2.83 (3H), 3.54 (2H), 3.71 (IH), 4.09 (IH), 4.27 (IH), 4.91 (IH), 4.96 (IH), 5.21 (3H), 5.72 (IH), 6.25 (IH), 6.69 (2H), 7.23 (IH), 7.36 (IH), 7.67 (IH), 7.82 (IH), 7.96 (IH), 8.11 (IH) ppm.
Example EL28 1 l-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic 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]-2-nitro-phenyl ester
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
Analogously to Example EL12b, 273 mg (387 μmol) 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
(178 μmol, 46%) of the title compound is isolated.
Example EL28 1 l-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7- allyl-4-hydroxy-5,5,9, 13-tetramethyl-l 6-(2-mefhyl-benzothiazol-5-yl)-2,6-dioxo- oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-2-nitro-phenyl ester
Analogously to Example ELI, 196 mg (178 μmol) of the compound that is prepared according to Example EL28a is reacted, and after working-up and purification, 100 mg (101 μmol, 57%) of the title compound is isolated.
1H-NMR (CDCI3): δ = 1.03 (3H), 1.06 (3H), 1.23 (3H), 1.70 (3H), 0.99-1.81 (21H), 1.91 (IH), 2.27-2.53 (6H), 2.63 (2H), 2.83 (3H), 2.88 (IH), 2.95 (IH), 3.51 (2H), 3.56 (IH), 4.00 (IH), 4.92 (IH), 4.98 (IH), 5.13-5.26 (4H), 5.71 (IH), 5.83 (IH), 6.68 (2H), 7.23 (IH), 7.34 (IH), 7.67 (IH), 7.79 (IH), 7.95 (IH), 8.13 (IH) ppm.
Example EL29
1 l-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic acid 4-
(lS,3S,7S,10R,llS,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 (A) and ll-(2,5-Dioxo-2,5-dihydro- pyrrol-l-yl)-undecanoic acid 4-(lR,3S,7S,10R,l IS,
12S, 16S)-[ 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-nitro- phenyl ester (B)
Analogously to Example EL2, 100 mg (101 μmol) of the compound that is prepared according to Example EL 19 is reacted, and after working-up and purification, 21 mg (21 μmol, 21%) of title compound A as well as 2 mg (2 μmol, 2%) of title compound B are isolated. H-NMR (CDC13) of A: δ = 0.97 (3H), 1.04 (3H), 1.23 (3H), 0.84-1.84 (24H), 1.71 (3H), 2.15 (2H), 2.23-2.68 (5H), 2.71 (IH), 2.83 (3H), 3.50 (2H), 3.71 (IH), 4.09 (IH), 4.27 (IH), 4.91 (IH), 4.96 (IH), 5.19 (2H), 5.23 (IH), 5.72 (IH), 6.26 (IH), 6.68 (2H), 7.23 (IH), 7.36 (IH), 7.66 (IH), 7.83 (IH), 7.97 (IH), 8.12 (IH) ppm.
Example EL30
4-(2,5-Dioxo-2,5-dihydro-pyrrol- 1 -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 EL30a
4-(2,5-Dioxo-2,5-dihydro-pyrrol-l -yl)-butanoic acid 4-(4S,7R,8S,9S, 13Z, 16S)-[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-yloxycarbonyloxymethyl]- phenyl ester
Analogously to Example EL 12b, 218 mg (309 μmol) 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 μmol, 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
Analogously to Example ELI, 103 mg (118 μmol) of the compound prepared according to Example EL30a are reacted. After working-up and purification, 13 mg (15 μmol, 13%) of the title compound are isolated.
1H-NMR (CDC13): δ= 0.88-1.84 (7H), 1.00 (3H), 1.12 (3H), 1.14 (3H), 1.71 (3H), 2.04 (2H), 2.23-2.71 (8H), 2.74 (3H), 2.99 (IH), 3.40 (IH), 3.67 (3H), 4.48 (IH), 4.76 (IH), 5.00 (IH), 5.04 (IH), 5.18 (IH), 5.55 (IH), 5.71 (IH), 5.98 (IH), 6.72 (2H), 7.01 (2H), 7.08 (2H), 7.37 (IH), 7.76 (IH), 7.96 (IH) ppm.
Example EL31
4-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-butanoic acid 4-(lS,3S,7S,10R,llS,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] -phenyl ester
Analogously to Example EL2, 13 mg (15 μmol) of the compound prepared according to Example EL30 are reacted. After working-up and purification, 5.7 mg (6.6 μmol,
44%) of the title compound are isolated.
1H-NMR (CDCI3) of A: δ - 1.04 (3H), 1.14 (3H), 1.16 (3H), 1.32 (3H), 1.34-1.84 (6H), 2.04 (2H), 2.15-2.75 (10H), 2.78 (3H), 2.85 (IH), 3.44 (IH), 3.67 (3H), 4.48
(IH), 4.73 (IH), 5.01 (IH), 5.05 (IH), 5.47 (IH), 5.70 (IH), 6.07 (IH), 6.72 (2H), 7.02
(2H), 7.13 (2H), 7.31 (IH), 7.77 (IH), 7.93 (IH) ppm.
Example EL32 6-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-hexanoic 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 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 Analogously to Example EL 12b, 218 mg (309 μmol) 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 μmol, 51%) of the title compound are isolated.
Example EL32
6-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-hexanoic cid 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 Analogously to Example ELI, 157 mg (159 μmol) of the compound prepared according to Example EL32a are reacted. After working-up and purification, 32 mg (37 μmol, 23%) of the title compound are isolated.
1H-NMR (CDC13): δ = 0.99 (3H), 1.12 (3H), 1.14 (3H), 1.04-2.84 (20H), 1.70 (3H), 2.75 (3H), 3.00 (IH), 3.40 (IH), 3.55 (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), 6.69 (2H), 6.98 (2H), 7.07 (2H), 7.37 (IH), 7.76 (2H), 7.96 (IH) ppm.
Example EL33
6-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-hexanoic acid 4-(lS,3S,7S,10R,l lS,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 Analogously to Example EL2, 30 mg (34 μmol) of the compound prepared according to Example EL32 are reacted. After working-up and purification, 13 mg (15 μmol, 44%) of the title compound are isolated. 1H-NMR (CDC13) of A: δ = 1.01 (3H), 1.13 (3H), 1.14 (3H), 1.32 (3H), 1.07-2.75 (22H), 2.78 (3H), 2.85 (IH), 3.44 (IH), 3.55 (2H), 3.69 (IH), 4.48 (IH), 4.73 (IH), 5.01 (IH), 5.05 (IH), 5.45 (IH), 5.70 (IH), 6.08 (IH), 6.69 (2H), 6.99 (2H), 7.12 (2H), 7.32 (IH), 7.77 (IH), 7.92 (IH) ppm.
Example EL34
1 l-(2,5-Dioxo-2,5-dihydro-ρyrrol-l-yl)-undecanoic 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 EL34a
1 l-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[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-yloxycarbonyloxymethyι] - phenyl ester
Analogously to Example EL 12b, 218 mg (309 μmol) 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 μmol, 24%) of the title compound are isolated.
Example EL34
1 l-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic 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
Analogously to Example ELI, 77 mg (73 μmol) of the compound prepared according to Example EL34a are reacted. After working-up and purification, 14 mg (15 μmol, 20%) of the title compound are isolated. 1H-NMR (CDC13): δ = 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 Analogously to Example EL2, 14 mg ( 15 μmol) of the compound prepared according to Example EL34 are reacted. After working-up and purification, 6 mg ( 6 μmol, 42%) of the title compound are isolated.
1H-NMR (CDCI3) vόn A: δ = 1.01 (3H), 1.14 (6H), 1.20-1.90 (26H), 2.12-2.58 (8H), 2.71 (IH), 2.77 (3H), 2.85 (IH), 3.44 (IH), 3.51 (2H), 3.69 (IH), 4.48 (IH), 4.73 (IH), 5.01 (IH), 5.05 (IH), 5.45 (IH), 5.70 (IH), 6.08 (IH), 6.68 (2H), 6.99 (2H), 7.12 (2H), 7.31 (IH), 7.77 (IH), 7.92 (IH) ppm.
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
Analogously to Example EL12b, 330 mg (470 μmol) 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 μmol,
38%) 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 Analogously to Example ELI, 170 mg (178 μmol) of the compound prepared according to Example EL36a are reacted. After working-up and purification, 21 mg (24 μmol, 14%) of the title compound are isolated.
1H-NMR (CDC13): δ = 1.02 (3H), 1.07 (3H), 1.22 (3H), 0.97-2.13 (8H), 1.70 (3H), 2.28-2.63 (8H), 2.84 (3H), 2.82-2.95 (2H), 3.55 (IH), 3.67 (2H), 3.97 (IH), 4.92 (IH), 4.96 (IH), 5.15 (IH), 5.16 (2H), 5.22 (IH), 5.70 (IH), 5.82 (IH), 6.68 (2H), 7.08 (2H), 7.34 (IH), 7.41 (2H), 7.79 (IH), 7.94 (IH) ppm.
Example EL37
4-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-butanoic acid 4-(lS,3S,7S,10R,l lS,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 -nitro-phenyl ester
(A) and
4-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-butanoic acid 4-(lR,3S,7S,10R,l 1S,12S,16S)-
[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] -phenyl ester (B)
32 mg (38μmol) of the compound prepared according to Example EL36 are reacted.
After working-up and purification, 10.1 mg ( 12 μmol, 31%) of title compound A as well as 1.2 mg (1.4 μmol, 3,7%) of title compound B are isolated.
Η-NMR (CDC13) of A: δ = 0.96 (3H), 1.04 (3H), 1.24 (3H), 1.29 (3H), 0.90-1.78 (7H), 2.04 (2H), 2.16 (2H), 2.20-2.62 (6H), 2.72 (IH), 2.84 (3H), 3.67 (2H), 3.69 (IH),
4.07 (IH), 4.20 (IH), 4.91 (IH), 4.95 (IH), 5.14 (2H), 5.22 (IH), 5.72 (IH), 6.24 (IH),
6.71 (2H), 7.10 (2H), 7.37 (IH), 7.40 (2H), 7.88 (IH), 7.97 (IH) ppm.
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
Example EL38a 6-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-hexanoic 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
Analogously to Example ELI 2b, 450 mg (640 μmol) 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 μmol,
17%) of the title compound are isolated.
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 μmol) 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. After 16 hours the mixture is diluted with dichloromethane and poured into a saturated solution of sodium bicarbonate. The mixture is extracted several times with dichloromethane and the combined organic extracts are dried over sodium sulfate. The residue obtained by filtration and removal of the solvent is purified by chromatography on fine silica gel. 64 mg (73 μmmol, 67%) of the title compound are isolated. 1H-NMR (CDC13): δ = 1.02 (3H), 1.07 (3H), 1.16 (3H), 1.70 (3H), 0.98-1.96 (12H), 2.25-2.58 (8H), 2.83 (3H), 2.90 (2H), 3.55 (3H), 3.97 (IH), 4.92 (IH), 4.96 (IH), 5.15 (IH), 5.16 (2H), 5.22 (IH), 5.70 (IH), 5.82 (IH), 6.69 (2H), 7.08 (2H), 7.34 (IH), 7.41 (2H), 7.79 (IH), 7.94 (IH) ppm.
Example EL39 6-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-hexanoic 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] -phenyl ester (A) und 6-(2,5-Dioxo-2,5-dihydro-pyrrol-l -yl)-hexanoic acid 4-(lR,3 S,7S, 10R,11 S, 12S, 16S)- [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] -phenyl ester (B)
Analogously to Example EL2, 64 mg (73 μmol) of the compound prepared according to Example EL38 are reacted. After working-up and purification, 25 mg (28 μmol, 39%) of the title compound A as well as 5.4 mg (6.1 μmol, 8.3%) of the title compound B are isolated. 1H-NMR (CDCI3) of A: δ = 0.96 (3H), 1.04 (3H), 1.13-1.82 (13H), 1.23 (3H), 1.29 (3H), 2.15 (2H), 2.22-2.64 (6H), 2.71 (IH), 2.84 (3H), 3.54 (2H), 3.69 (IH), 4.08 (IH), 4.20 (IH), 4.91 (IH), 4.95 (IH), 5.14 (2H), 5.22 (IH), 5.72 (IH), 6.24 (IH), 6.69 (2H), 7.07 (2H), 7.37 (IH), 7.40 (2H), 7.82 (IH), 7.97 (IH) ppm.
Example EL40
1 l-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic 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 EL40a
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-16-(2-methyl- benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]- phenyl ester
Analogously to Example EL 12b, 450 mg (640 μmol) 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 μmol, 10%) of the title compound are isolated.
Example EL40
1 l-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic 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
Analogously to Example EL38, 67 mg (63 μmol) of the compound prepared according to Example EL40a are reacted. After working-up and purification, 23 mg (24 μmol,
38%) of the title compound are isolated.
1H-NMR (CDC13): δ = 1.02 (3H), 1.07 (3H), 1.21 (3H), 1.70 (3H), 0.99-1.81 (21H), 1.91 (IH), 2.27-2.58 (8H), 2.83 (3H), 2.89 (2H), 3.50 (2H), 3.55 (IH), 3.97 (IH), 4.92
(IH), 4.96 (IH), 5.15 (IH), 5.16 (2H), 5.20 (IH), 5.70 (IH), 5.82 (IH), 6.68 (2H), 7.08
(2H), 7.34 (IH), 7.41 (2H), 7.79 (IH), 7.94 (IH) ppm.
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-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-l 1- yloxycarbonyloxymethyl]-phenyl ester (B)
Analogously to Example EL2, 33 mg (35 μmol) of the compound prepared according to Example EL40 are reacted. After working-up and purification, 13 mg (14 μmol, 38%) of the title compound A as well as 4 mg (4 μmol, 12%) of the title compound B are isolated.
1H-NMR (CDC13) of A: δ = 0.96 (3H), 1.04 (3H), 1.23 (3H), 0.91-1.78 (27H), 2.16 (2H), 2.23-2.68 (5H), 2.71 (IH), 2.84 (3H), 3.50 (2H), 3.69 (IH), 4.07 (IH), 4.20 (IH), 4.91 (IH), 4.95 (IH), 5.14 (2H), 5.22 (IH), 5.72 (IH), 6.24 (IH), 6.68 (2H), 7.07 (2H), 7.37 (IH), 7.40 (2H), 7.82 (IH), 7.97 (IH) ppm.
Example EL42
4-(2,5-Dioxo-2,5-dihydro-pyrrol- 1 -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]-2-chlor-phenyl ester
Example EL42a
4-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-butanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[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-yloxycarbonyloxymethyl]-2- chlor-phenyl ester
Analogously to Example EL12b, 329 mg (467μmol) 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 μmol,
27%) of the title compound are isolated.
Example EL42
4-(2,5-Dioxo-2,5-dihydro-pyrrol- 1 -yl)-butanoic acid 4-(4S,7R,8S,9S, 13Z, 16S)-[7- allyl-8-hydroxy-5,5,9, 13-tetramethyl-l 6-(2-methyl-benzothiazol-5-yl)-2,6-dioxo- oxacyclohexadec-13-en-4-yloxycarbonyloxymethyl]-2-chlor-phenyl ester Analogously to Example ELI, 126 mg (127 μmol) of the compound prepared according to Example EL42a are reacted. After working-up and purification, 79 mg (90 μmol, 71%) of the title compound are isolated. 1H-NMR (CDCI3): δ = 1.01 (3H), 1.13 (3H), 1.14 (3H), 1.70 (3H), 1.31-1.72 (17H), 2.75 (3H), 2.99 (IH), 3.40 (IH), 3.68 (3H), 4.49 (IH), 4.70 (IH), 5.00 (IH), 5.05 (IH), 5.18 (IH), 5.55 (IH), 5.71 (IH), 5.98 (IH), 6.72 (2H), 6.99 (IH), 7.07 (IH), 7.10 (IH), 7.36 (IH), 7.75 (IH), 7.95 (IH) ppm. Example EL43
4-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-butanoic acid 4-(lS,3S,7S,10R,l lS,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-chlor-phenyl ester
(A) and 4-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-butanoic acid 4-
(1R,3S,7S,10R,11S,12S, 16S)-[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-7- yloxycarbonyloxymethyl]-2-chlor-phenyl ester (B) Analogously to Example EL2, 66 mg (75 μmol) of the compound prepared according to Example EL42 are reacted. After working-up and purification, 29.4 mg (32.9μmol,
44%) of the title compound A as well as 9.7 mg (10.9 μmol, 14%) of the title compound B are isolated.
1H-NMR (CDC13) of A: δ = 1.03 (3H), 1.13 (3H), 1.15 (3H), 1.23 (IH), 1.31 (3H), 1.34-2.74 (17H), 2.78 (3H), 2.86 (IH), 3.44 (IH), 3.67 (3H), 4.46 (IH), 4.67 (IH),
5.01 (IH), 5.05 (IH), 5.46 (IH), 5.70 (IH), 6.08 (IH), 6.72 (2H), 7.01 (IH), 7.08 (IH),
7.16 (IH), 7.31 (IH), 7.77 (IH), 7.92 (IH) ppm.
Example EL44 6-(2,5-Dioxo-2,5-dihydro-pyrrol-l -yl)-hexanoic 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]-2-chloro-ρhenyl ester
Example EL44a 6-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-hexanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[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-yloxycarbonyloxymethyl]-2- chloro-phenyl ester
Analogously to Example EL12b, 329 mg (467 μmol) 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 μmol,
25%) of the title compound are isolated. Example EL44
6-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-hexanoic 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]-2-chloro-phenyl ester Analogously to Example ELI, 120 mg (118 μmol) of the compound prepared according to Example EL44a are reacted. After working-up and purification, 60 mg (66 μmol, 56%) of the title compound are isolated.
1H-NMR (CDCI3): δ = 1.01 (3H), 1.05 (IH), 1.13 (3H), 1.14 (3H), 1.33-1.89 (12H), 1.71 (3H), 2.24-2.70 (8H), 2.74 (3H), 3.00 (IH), 3.40 (IH), 3.55 (2H), 3.69 (IH), 4.49 (IH), 4.71 (IH), 5.00 (IH), 5.05 (IH), 5.18 (IH), 5.56 (IH), 5.71 (IH), 5.99 (IH), 6.70 (2H), 6.95 (IH), 7.03 (IH), 7.11 (IH), 7.37 (IH), 7.75 (IH), 7.95 (IH), ppm.
Example EL45
6-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-hexanoic 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]-2-chloro-phenyl ester (A) and 6-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-hexanoic acid 4- (1R,3S,7S,10R,11S,12S, 16 S)-[l 0-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- yloxycarbonyloxymethyl]-2-chloro-phenyl ester (B)
Analogously to Example EL2, 60 mg (66 μmol) of the compound prepared according to Example EL44 is reacted. After working-up and purification, 32 mg (34.7 μmol, 53%) of the title compound A as well as 11 mg (11.9 μmol, 18%) of the title compound B are isolated. 1H-NMR (CDC13) von A: δ = 1.02 (3H), 1.14 (3H), 1.15 (3H), 1.24 (IH), 1.32 (3H), 1.34-2.74 (21H), 2.77 (3H), 2.86 (IH), 3.44 (IH), 3.55 (2H), 3.69 (IH), 4.46 (IH), 4.67 (IH), 5.01 (IH), 5.05 (IH), 5.46 (IH), 5.70 (IH), 6.09 (IH), 6.69 (2H), 6.99 (IH), 7.04 (IH), 7.16 (IH), 7.32 (IH), 7.77 (IH), 7.92 (IH) ppm.
Example EL46
1 l-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic 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]-2-chloro-phenyl ester Example EL46a
1 l-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[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-yloxycarbonyloxymethyl]-2- chloro-phenyl ester
Analogously to Example EL 12b, 323 mg (459 μmol) 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$ μmol, 19%) of the title compound are isolated.
Example EL46
1 l-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic 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]-2-chlor-phenyl ester
Analogously to Example ELI, 59 mg (54 μmol) of the compound prepared according to Example EL46a are reacted. After working-up and purification, 27 mg (27.7 μmol,
51%) of the title compound are isolated.
*H-NMR (CDC13): δ = 1.01 (3H), 1.13 (3H), 1.15 (3H), 1.23-2.70 (31H), 1.71 (3H), 2.74 (3H), 2.99 (IH), 3.40 (IH), 3.51 (2H), 3.68 (IH), 4.49 (IH), 4.70 (IH), 5.00 (IH),
5.04 (IH), 5.18 (IH), 5.56 (IH), 5.71 (IH), 5.99 (IH), 6.68 (2H), 6.95 (IH), 7.03 (IH),
7.11 (IH), 7.36 (IH), 7.75 (IH), 7.95 (IH) ppm.
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-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-7- yloxycarbonyloxymethyl]-2-chloro-phenyl ester (B)
Analogously to Example EL2, 27 mg (27 μmol) of the compound prepared according to Example EL46 are reacted. After working-up and purification, 14 mg (14.1 μmol, 52%) of the title compound A as well as 5 mg (5.0 μmol, 19%) of the title compound B are isolated.
1H-NMR (CDCI3) of A: δ = 1.02 (3H), 1.13 (3H), 1.15 (3H), 1.19-1.84 (27H), 2.09- 2.74 (8H), 2.77 (3H), 2.85 (IH), 3.44 (IH), 3.50 (2H), 3.69 (IH), 4.46 (IH), 4.67 (IH), 5.01 (IH), 5.06 (IH), 5.45 (IH), 5.70 (IH), 6.08 (IH), 6.68 (2H), 6.99 (IH), 7.04 (IH), 7.16 (IH), 7.31 (IH), 7.76 (IH), 7.91 (lH) ppm.
Example EL48
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] -2-chloro-phenyl ester
Example EL48a
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]-2- chloro-phenyl ester
Analogously to Example EL12b, 340 mg (482 μmol) 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 μmol,
32%) of the title compound are isolated.
Example EL48
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]-2-chloro-phenyl ester Analogously to Example ELI, 151 mg (152 μmol) of the compound prepared according to Example EL48a are reacted. After working-up and purification, 46 mg (52 μmol, 34%) of the title compound are isolated. 1H-NMR (CDCI3): δ = 1.02 (3H), 1.07 (3H), 1.26 (3H), 1.71 (3H), 1.15-2.44 (13H), 2.51 (2H), 2.65 (2H), 2.84 (3H), 2.91 (IH), 3.55 (IH), 3.68 (2H), 3.99 (IH), 4.92 (IH), 4.98 (IH), 5.06-5.25 (4H), 5.70 (IH), 5.83 (IH), 6.72 (2H), 7.17 (IH), 7.31 (IH), 7.34 (IH), 7.49 (IH), 7.80 (IH), 7.96 (IH) ppm. Example EL49
4-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-butanoic acid 4-(lS,3S,7S,10R,l lS,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-chloro-phenyl ester (A) and 4-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-butanoic acid 4-
(lR,3S,7S,10R,l lS,12S,16S)-[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-chloro-phenyl ester (B) Analogously to Example EL2, 46 mg (52 μmol) of the compound prepared according to Example EL48 are reacted. After working-up and purification, 6 mg (6.7 μmol,
13%) of the title compound A as well as 1 mg (1.1 μmol, 2%) of the title compound B are isolated.
1H-NMR (CDC13) of A: δ = 0.97 (3H), 1.04 (3H), 1.24 (3H), 1.30 (3H), 1.14-2.76 (21H), 2.85 (3H), 3.68 (3H), 4.09 (IH), 4.23 (IH), 4.91 (IH), 4.97 (IH), 5.11 (2H),
5.22 (IH), 5.72 (IH), 6.25 (IH), 6.72 (2H), 7.16 (IH), 7.30 (IH), 7.37 (IH), 7.48 (IH),
7.83 (IH), 7.99 (IH) ppm.
Example EL50 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]-2-chloro-phenyl ester
Example EL50a 6-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-hexanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7- allyl-4-(tert-butyl-dimetlιyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl- benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-2- chloro-phenyl ester
Analogously to Example ELI 2b, 340 mg (482 μmol) 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 μmol,
32%) of the title compound are isolated. Example EL50
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]-2-chloro-phenyl ester Analogously to Example ELI, 158 mg (155 μmol) of the compound prepared according to Example EL50a are reacted. After working-up and purification, 58 mg (64 μmol, 41%) of the title compound are isolated.
1H-NMR (CDC13): δ = 1.02 (3H), 1.08 (3H), 1.22 (3H), 1.71 (3H), 0.90-2.45 (17H), 2.51 (2H), 2.61 (2H), 2.83 (3H), 2.88 (IH), 3.55 (3H), 3.97 (IH), 4.92 (IH), 4.98 (IH), 5.10-5.25 (4H), 5.71 (IH), 5.83 (IH), 6.69 (2H), 7.12 (IH), 7.30 (IH), 7.34 (IH), 7.49 (IH), 7.79 (IH), 7.95 (IH) ppm.
Example EL51
6-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-hexanoic 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- 11 -yloxycarbonyloxymethyl] -2-chloro-phenyl ester (A) and 6-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-hexanoic acid 4- (lR,3S,7S,10R,l lS,12S,16S)-[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-chloro-phenyl ester (B)
Analogously to Example EL2, 58 mg (64 μmol) of the compound prepared according to Example EL50 are reacted. After working-up and purification, 25 mg (27 μmol, 42%) of the title compound A as well as 7 mg (7.6 μmol, 12%) of the title compound B are isolated. 1H-NMR (CDC13) of A: δ = 0.97 (3H), 1.04 (3H), 1.24 (3H), 1.31 (3H), 1.12-2.65 (21H), 2.72 (IH), 2.84 (3H), 3.55 (2H), 3.71 (IH), 4.08 (IH), 4.22 (IH), 4.91 (IH), 4.96 (IH), 5.12 (2H), 5.23 (IH), 5.72 (IH), 6.24 (IH), 6.69 (2H), 7.13 (IH), 7.30 (IH), 7.37 (IH), 7.48 (IH), 7.83 (IH), 7.97 (IH) ppm.
Example EL52
1 l-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic 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]-2-chloro-phenyl ester Example EL52a
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- 16-(2-methyl- benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-2- chloro-phenyl ester
Analogously to Example EL 12b, 355 mg (476 μmol) 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 μmol, 24%) of the title compound are isolated.
Example EL52
1 l-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic 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]-2-chloro-phenyl ester
Analogously to Example ELI, 122 mg (112 μmol) of the compound prepared according to Example EL52a are reacted. After working-up and purification, 28 mg
(29 μmol, 26%) of the title compound are isolated.
1H-NMR (CDC13): δ = 1.02 (3H), 1.08 (3H), 1.22 (3H), 1.11-2.48 (26H), 1.71 (3H), 2.51 (2H), 2.61 (2H), 2.83 (3H), 2.89 (IH), 3.46-3.58 (3H), 3.98 (IH), 4.61 (2H), 4.92
(IH), 4.98 (IH), 5.11-5.25 (3H), 5.70 (IH), 5.83 (IH), 6.68 (2H), 7.00 (IH), 7.18 (IH),
7.29 (IH), 7.36 (IH), 7.79 (IH), 7.95 (IH) ppm.
Example EL53 l l-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic acid 4-(lS,3S,7S,10R,llS,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-chloro- phenyl ester (A) and ll-(2,5-Dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoic 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-dioxo-4, 17-dioxa-bicyclo [14.1.0]heptadec- 11 - yloxycarbonyloxymethyl]-2-chloro-phenyl ester (B)
Analogously to Example EL2, 28 mg (29 μmol) of the compound prepared according to Example EL52 are reacted. After working-up and purification, 6.2 g (6.3 μmol, 22%) of the title compound A as well as 0.3 mg (0.3 μmol, 1%) of the title compound B are isolated.
1H-NMR (CDC13) of A: δ = 0.97 (3H), 1.04 (3H), 1.23 (3H), 0.82-1.83 (25H), 2.16 (2H), 2.24-2.65 (7H), 2.72 (IH), 2.84 (3H), 3.50 (2H), 3.70 (IH), 4.08 (IH), 4.21 (IH), 4.92 (IH), 4.97 (IH), 5.11 (2H), 5.22 (IH), 5.72 (IH), 6.25 (IH), 6.67 (2H), 7.12 (IH), 7.30 (IH), 7.37 (IH), 7.49 (IH), 7.83 (IH), 7.98 (IH) ppm.
Example EL54
(4S,7R,8S,9S,13Z,16S)-Carbonic 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 4-[4-(2,5- dioxo-2,5-dihydro-pyrrol-l-yl)-3-nitro-butyrylamino]-benzyl ester
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
Analogously to Example ELI 2b, 160 mg (227 μmol) 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 μmol, 27%) of the title compound are isolated.
1H-NMR (CDCI3): δ = 0.07 (3H), 0.12 (3H), 0.92 (9H), 0.99 (3H), 1.03 (3H), 1.23 (3H), 0.85-1.74 (8H), 1.93 (IH), 2.28 (IH), 2.38 (2H), 2.49 (IH), 2.66 (IH), 2.77 (3H), 2.82 (IH), 2.97 (IH), 3.22 (IH), 3.87 (IH), 4.85-5.03 (4H), 5.22 (IH), 5.42 (IH), 5.74 (IH), 5.89 (IH), 6.10 (2H), 6.68 (IH), 7.19 (IH), 7.32 (IH), 7.73 (IH), 7.90 (IH), 7.98 (IH) ppm.
Example EL54b
(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-l 3- en-4-yl ester 4-[4-(2,5-dioxo-2,5-dihydro-pyrrol-l-yl)-butyryIamino]-3-nitro-benzyl ester
153 mg (837 μmol) of the compound prepared according to Example L4 are mixed with 1.82 ml thionyl chloride and refluxed for 3.5 hours. The mixture is diluted with toluene and evaporated. A solution of 130 mg (156 μmol) of the compound prepared according to Example 54a in 6 ml dichloromethane is added, 75 μl pyridine are admixed, and the mixture is stirred at 23 °C for 16 hours. It is poured into water, extracted several times with dichloromethane, the combined organic extracts are washed with water and dried over sodium sulfate. After filtration and removal of the solvent, the residue is purified by chromatography. 101 mg (101 μmol, 65%) 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 Analogously to Example ELI, 101 mg (101 μmol) of the compound prepared according to Example EL54a are reacted. After working-up and purification, 62 mg (70 μmol, 69%) of the title compound are isolated.
1H-NMR (CDC13): δ = 1.01 (3H), 1.14 (6H), 1.39 (2H), 1.64 (2H), 1.71 (3H), 1.80 (2H), 2.07 (2H), 2.23-2.54 (8H), 2.69 (IH), 2.77 (3H), 2.96 (IH), 3.39 (IH), 3.65 (2H), 3.69 (IH), 4.52 (IH), 4.75 (IH), 5.00 (IH), 5.05 (IH), 5.18 (IH), 5.55 (IH), 5.71 (IH), 5.98 (IH), 6.71 (2H), 7.31 (IH), 7.36 (IH), 7.77 (IH), 7.91 (IH), 7.93 (IH), 8.67 (IH), 10.28 (IH) ppm.
Example EL55
(1S,3S,7S,10R,11S,12S,16R)-Carbonic acid 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-yl ester 4-[4-(2,5-dioxo-2,5-dihydro-pyrrol-l-yl)- butyrylamino]-3-nitro-benzyl ester (A) and (1R,3S,7S,10R,11S,12S,16S)-Carbonic acid 10-allyl- 11 -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-[4-(2,5-dioxo-2,5-dihydro- pyrrol-l-yl)-butyrylamino]-3-nitro-benzyl ester (B) Analogously to Example EL2, 62 mg (70 μmol) of the compound prepared according to Example EL54 are reacted. After working-up and purification, 38 mg (42 μmol, 60%) of the title compound A as well as 11 mg (12 μmol, 17%) of the title compound B are isolated. Η-NMR (CDC13) of A: δ = 1.03 (3H), 1.13 (3H), 1.17 (3H), 1.32 (3H), 1.20-2.58 (17H), 2.70 (IH), 2.79 (3H), 2.85 (IH), 3.43 (IH), 3.65 (2H), 3.69 (IH), 4.52 (IH), 4.72 (IH), 5.01 (IH), 5.05 (IH), 5.45 (IH), 5.70 (IH), 6.07 (IH), 6.71 (2H), 7.31 (IH), 7.35 (IH), 7.78 (IH), 7.88 (IH), 7.95 (IH), 8.68 (IH), 10.28 (IH) ppm.
Example EL56
(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-[6-(2,5- dioxo-2,5-dihydro-pyrrol- 1 -yl)-hexanoylamino]-3-nitro-benzyl ester
Example EL56a
(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-[6-(2,5-dioxo-2,5-dihydro-pyrrol-l -yl)-hexanoylamino]-3-nitro-benzyl ester
Analogously to Example EL54b, 50 mg (60 μmol) 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 μmol, 94%) of the title compound are isolated.
Example EL56
(4S,7R,8S,9S, 13Z, 16S)-Carbonic 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 4-[6-(2,5- dioxo-2,5-dihydro-pyrrol-l-yl)-hexanoylamino]-3-nitro-benzyl ester Analogously to Example ELI, 82 mg (80 μmol) of the compound prepared according to Example EL56a are reacted. After working-up and purification, 34 mg (37 μmol, 46%) of the title compound are isolated.
1H-NMR (CDC13): δ = 1.01 (3H), 1.14 (6H), 1.70 (3H), 1.31-2.57 (20H), 2.69 (IH), 2.78 (3H), 2.97 (IH), 3.39 (IH), 3.54 (2H), 3.69 (IH), 4.51 (IH), 4.74 (IH), 5.00 (IH), 5.05 (IH), 5.18 (IH), 5.55 (IH), 5.78 (IH), 5.98 (IH), 6.69 (2H), 7.31 (IH), 7.36 (IH), 7.76 (IH), 7.92 (IH), 7.93 (IH), 8.71 (IH), 10.32 (IH) ppm.
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-7-yl ester 4-[6-(2,5-dioxo-2,5-dihydro- pyrrol-l-yl)-hexanoylamino]-3-nitro-benzyl ester (B)
Analogously to Example EL2, 34 mg (37 μmol) of the compound prepared according to Example EL56 are reacted. After working-up and purification, 19 mg (20.4 μmol, 55%) of the title compound A as well as 6 mg (6.4 μmol, 17%) of the title compound B are isolated.
1H-NMR (CDC13) of A: δ = 1.02 (3H), 1.14 (3H), 1.15 (3H), 1.39 (2H), 1.70 (3H), 1.65 (2H), 1.80 (2H), 2.06 (2H), 2.23-2.55 (8H), 2.69 (IH), 2.77 (3H), 2.97 (IH), 3.39 (IH), 3.65 (2H), 3.69 (IH), 4.52 (IH), 4.75 (IH), 5.00 (IH), 5.05 (IH), 5.18 (IH), 5.55 (IH), 5.71 (IH), 5.97 (IH), 6.71 (2H), 7.31 (IH), 7.36 (IH), 7.76 (IH), 7.91 (IH), 7.93 (IH), 8.68 (IH), 10.28 (lH) ppm.
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-[ll-(2,5- dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoylamino]-3-nitro-benzyl ester
Example EL58a
(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-l 3- en-4-yl ester 4-[l l-(2,5-dioxo-2,5-dihydro-pyrrol-l-yl)-undecanoylamino]-3-nitro- benzyl ester
Analogously to Example EL54b, 130 mg (156 μmol) 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 μmol, 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 Analogously to Example ELI, 120 mg (109 μmol) of the compound prepared according to Example EL58a are reacted. After working-up and purification, 89 mg (90 μmol, 83%) of the title compound are isolated.
1H-NMR (CDC13): δ = 1.01 (3H), 1.13 (3H), 1.14 (3H), 1.70 (3H), 1.04-2.56 (30H), 2.69 (IH), 2.78 (3H), 2.97 (IH), 3.39 (IH), 3.50 (2H), 3.69 (IH), 4.52 (IH), 4.74 (IH), 5.01 (IH), 5.05 (IH), 5.18 (IH), 5.55 (IH), 5.71 (IH), 5.97 (IH), 6.67 (2H), 7.31 (IH), 7.36 (IH), 7.76 (IH), 7.91 (IH), 7.93 (IH), 8.72 (IH), 10.33 (IH) ppm.
Example EL59
(1S,3S,7S,10R,1 lS,12S,16R)-Carbonic acid 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-yl ester 4-[l l-(2,5-dioxo-2,5-dihydro-pyrrol-l-yl)- undecanoylamino]-3-nitro-benzyl ester (A) and (1R,3S,7S,10R,11S,12S,16S)- Carbonic acid 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-yl ester 4-[ll-(2,5-dioxo-2,5- dihydro-pyrrol-l-yl)-undecanoylamino]-3-nitro-benzyl ester (B) Analogously to Example EL2, 89 mg (90 μmol) of the compound prepared according to Example EL58 are reacted. After working-up and purification, 45 mg (μmol, %) of the title compound A as well as 15 mg (μmol, %) of the title compound B are isolated. 1H-NMR (CDC13) of A: δ = 1.03 (3H), 1.13 (3H), 1.16 (3H), 1.20-1.83 (26H), 2.09- 2.57 (8H), 2.72 (IH), 2.79 (3H), 2.86 (IH), 3.44 (IH), 3.50 (2H), 3.69 (IH), 4.51 (IH), 4.72 (IH), 5.01 (IH), 5.05 (IH), 5.45 (IH), 5.71 (IH), 6.08 (IH), 6.68 (2H), 7.32 (IH), 7.35 (IH), 7.78 (IH), 7.88 (IH), 7.96 (IH), 8.73 (IH), 10.33 (IH) ppm.
Example EL60
(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 6-(2,5-dioxo- 2,5-dihydro-pyrrol- 1 -yl)-hexyl ester
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 Analogously to 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 μmol, 8%) of the title compound are isolated.
Example EL60 (4S,7R,8S,9S,13Z,16S)-Carbonic 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 6-(2,5-dioxo-
2,5-dihydro-pyrrol-l-yl)-hexyl ester
Analogously to Example ELI, 101 mg (117 μmol) of the compound prepared according to Example EL60a are reacted. After working-up and purification, 68 mg (91 μmol, 77%) of the title compound are isolated.
1H-NMR (CDC13): δ = 1.02 (3H), 1.12-1.87 (19H), 1.70 (3H), 2.23-2.56 (6H), 2.66
(IH), 2.83 (3H), 2.97 (IH), 3.40 (2H), 3.48 (2H), 3.68 (IH), 3.75 (IH), 5.01 (IH), 5.05
(IH), 5.17 (2H), 5.51 (IH), 5.72 (IH), 5.97 (IH), 6.68 (2H), 7.35 (IH), 7.78 (IH), 7.92
(lH) ppm.
Example EL61
(1S,3S,7S,10R,1 lS,12S,16R)-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-7-yl ester 6-(2,5-dioxo-2,5-dihydro-pyrrol-l-yl)-hexyl 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-7-yl ester 6-(2,5-dioxo-2,5-dihydro-pyrrol-l-yl)-hexyl ester
(B)
Analogously to Example EL2, 68 mg (91 μmol) of the compound prepared according to Example EL60 are reacted. After working-up and purification, 26 mg (34 μmol,
37%) of the title compound A as well as 10 mg (13 μmol, 14%) of the title compound
B are isolated. 1H-NMR (CDCI3) of A: δ = 1.03 (3H), 1.14 (3H), 1.18 (3H), 1.32 (3H), 1.10-1.85 (15H), 2.11-2.43 (5H), 2.52 (IH), 2.70 (IH), 2.84 (3H), 2.86 (IH), 3.38-3.51 (4H), 3.69 (IH), 3.74 (IH), 5.01 (IH), 5.05 (IH), 5.42 (IH), 5.72 (IH), 6.07 (IH), 6.69 (2H), 7.32 (IH), 7.80 (IH), 7.90 (IH) ppm.
Example EL62
(4S,7R,8S,9S, 13Z, 16S)-Carbonic acid 7-allyl-4-hydroxy-5,5,9, 13-tetramethyl-l 6-(2- methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yl ester 4-[4-(2,5- dioxo-2,5-dihydro-pyrrol- 1 -yl)-3-nitro-butyrylamino]-benzyl ester
Example EL62a
(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-amino-benzyl ester Analogously to Example EL12b, 1.73 g (2.46 mmol) of the compound prepared according to Example EL14a are reacted with 2.06 g (4-amino-3-nitro-phenyl)- methanol. After working-up and purification, 420 mg (502 μmol, 20%) of the title compound are isolated. 1H-NMR (CDC13): δ = -0.10 (3H), 0.09 (3H), 0.84 (9H), 0.96-1.21 (2H), 1.01 (3H), 1.12 (3H), 1.15 (3H), 1.70 (3H), 1.61-1.85 (4H), 2.11 (IH), 2.29 (2H), 2.54-2.78 (3H), 2.83 (3H), 2.90 (IH), 3.31 (IH), 3.93 (IH), 4.86 (IH), 4.96 (IH), 5.04 (IH), 5.11 (IH), 5.25 (2H), 5.55 (IH), 5.72 (IH), 6.14 (2H), 6.82 (IH), 7.35 (IH), 7.43 (IH), 7.79 (IH), 7.91 (IH), 8.18 (IH) ppm.
Example EL62b
(4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-4-(tert-butyl-dimethyl-silanyloxy)- 5,5,9, 13-tetramethyl- 1 -(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-l 3- en-8-yl ester 4-[4-(2,5-dioxo-2,5-dihydro-pyrrol-l-yl)-butyrylamino]-3-nitro-benzyl ester Analogously to Example EL54b, 140 mg (167 μmol) of the compound prepared according to Example EL62a are reacted with the compound prepared according to Example L4. After working-up and purification, 150 mg (150 μmol, 90%) of the title compound are isolated. Example EL62
(4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-4-hydroxy-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)-3-nitro-butyrylamino]-benzyl ester
Analogously to Example ELI, 145 mg (145 μmol) of the compound prepared according to Example EL62a are reacted. After working-up and purification, 67 mg
(76 μmol, 52%) of the title compound are isolated.
1H-NMR (CDC13): δ = 1.02 (3H), 1.08 (3H), 1.22 (3H), 1.70 (3H), 1.09-2.12 (8H), 2.27-2.55 (8H), 2.83 (3H), 2.87 (2H), 3.56 (IH), 3.65 (2H), 3.99 (IH), 4.93 (IH), 4.98
(IH), 5.12-5.26 (4H), 5.71 (IH), 5.83 (IH), 6.70 (2H), 7.33 (IH), 7.67 (IH), 7.79 (IH),
7.94 (IH), 8.25 (IH), 8.79 (IH), 10.32 (IH) ppm.
Example EL63 (1S,3S,7S,10R,1 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-[4-(2,5-dioxo-2,5-dihydro-pyrrol-l-yl)-butyrylamino]-3-nitro-benzyl ester (A) and (1R,3S,7S,10R,11S,12S,16S)-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 1-yl ester 4-[4-(2,5-dioxo-2,5-dihydro-pyrrol-l-yl)- butyrylamino]-3-nitro-benzyl ester (B)
Analogously to Example EL2, 67 mg (76 μmol) of the compound prepared according to Example EL62 are reacted. After working-up and purification, 37 mg (41 μmol, 54%) of the title compound A as well as 12 mg (13 μmol, 18%) of the title compound B are isolated.
Example EL64
(4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-4-hydroxy-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)-3-nitro-hexanoylamino]-benzyl ester
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 Analogously to Example EL54b, 140 mg (167 μmol) 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 μmol, 90%) of the title compound are isolated.
Example EL64
(4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-4-hydroxy-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)-3-nitro-hexanoylamino]-benzyl ester Analogously to Example ELI, 150 mg (151 μmol) of the compound prepared according to Example EL64a are reacted. After working-up and purification, 68 mg (74 μmol, 49%) of the title compound are isolated.
1H-NMR (CDC13): δ = 1.02 (3H), 1.07 (3H), 1.23 (3H), 1.70 (3H), 1.16-2.54 (20H), 2.84 (3H), 2.87 (2H), 3.54 (3H), 3.98 (IH), 4.92 (IH), 4.98 (IH), 5.13-5.26 (4H), 5.71 (IH), 5.83 (IH), 6.68 (2H), 7.33 (IH), 7.67 (IH), 7.79 (IH), 7.94 (IH), 8.26 (IH), 8.82 (IH), 10.37 (lH) ppm.58
Example EL65
(1S,3S,7S,10R,1 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-[4-(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-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-yl ester 4-[4-(2,5-dioxo-2,5-dihydro-pyrrol-l-yl)- hexanoylamino]-3-nitro-benzyl ester (B) Analogously to Example EL2, 68 mg (74 μmol) of the compound prepared according to Example EL64 are reacted. After working-up and purification, 44 mg (47 μmol, 64%) of the title compound A as well as 3 mg (3 μmol, 4%) of the title compound B are isolated. Example EL66
(4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-4-hydroxy-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)-3-m*tro-undecanoylamino]-benzyl ester
Example EL66a
(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-l 3- en-8-yl ester 4-[4-(2,5-dioxo-2,5-dihydro-pyrrol-l-yl)- undecanoylamino]-3-nitro- benzyl ester
Analogously to Example EL54b, 140 mg (167 μmol) 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 μmol, 90%) of the title compound are isolated.
Example EL66
(4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2- methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-l 3-en-8-yl ester 4-[4-(2,5- dioxo-2,5-dihydro-pyrrol- 1 -yl)-3-nitro-undecanoylamino]-benzyl ester
Analogously to Example ELI, 145 mg (132 μmol) of the compound prepared according to Example EL66a are reacted. After working-up and purification, 106 mg
(108 μmol, 82%) of the title compound are isolated.
1H-NMR (CDC13): δ = 1.01 (3H), 1.06 (3H), 1.24 (3H), 1.70 (3H), 1.14-2.57 (30H), 2.82 (3H), 2.89 (2H), 3.50 (2H), 3.55 (IH), 4.01 (IH), 4.92 (IH), 4.99 (IH), 5.11-5.28
(4H), 5.70 (IH), 5.83 (IH), 6.69 (2H), 7.34 (IH), 7.67 (IH), 7.79 (IH), 7.96 (IH), 8.26
(IH), 8.85 (IH), 10.38 (IH) ppm.
Example EL67 (1S,3S,7S,10R,1 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-[4-(2,5-dioxo-2,5-dihydro-pyrrol-l-yl)- undecanoylamino]-3-nitro-benzyl ester (A) and (1R,3S,7S,10R,11S,12S,16S)-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 1-yl ester 4-[4-(2,5-dioxo-2,5-dihydro-pyrrol-l-yl)- undecanoylamino]-3-nitro-benzyl ester (B)
Analogously to Example EL2, 106 mg (108 μmol) of the compound prepared according to Example EL66 are reacted. After working-up and purification, 58 mg (58 μmol, 54%) of the title compound A as well as 6 mg (6 μmol, 6%) of the title compound B are isolated.
1H-NMR (CDCI3) of A: δ = 0.96 (3H), 1.04 (3H), 1.23 (3H), 1.31 (3H), 0.81-1.83
(23H), 2.16 (2H), 2.23-2.66 (6H), 2.71 (IH), 2.85 (3H), 3.5 (2H), 3.72 (IH), 4.08 (IH), 4.24 (IH), 4.92 (IH), 4.97 (IH), 5.15 (2H), 5.22 (IH), 5.72 (IH), 6.25 (IH), 6.68 (2H),
7.36 (IH), 7.66 (IH), 7.83 (IH), 7.97 (IH), 8.25 (IH), 8.83 (IH), 10.37 (IH) ppm.
Examples of the Synthesis of Effector-Linker Recognition Units (ELE)
Example ELE1
[3 -(3 -( AP39r)-Sulfanyl-2,5-dioxo-pyrrolidin- 1 -yl)-propyl] -carbamic acid- 10-allyl- 11 - 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
Example ELE la
Reduction of an Antibody Fragment with Terminal Cysteine A single-strand protein that consists of the variable domains of the heavy and light antibody chains (single-chain Fv, scFv) of the amino acid sequence ENQLLESGGGLNQPGGSLRLSCAASGFTFSSFSMSWNRQAPGKGLEWNSSISG SSGTTYYADSNKGRFTISRDΝSKΝTLYLQMΝSLRAEDTANYYCAKPFPYFDY WGQGTLNTNSSGDGSSGGSGGASEINLTQSPGTLSLSPGERATLSCRASQSNSS SFLAWYQQKPGQAPRLLIYYASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAN YYCQQTGRIPPTFGQGTKNEIKGGGCA, which specifically recognizes the fibronectin domain B (ED-B) and is referred to as AP39, is used for coupling after reduction of the c-terminal cysteine.
For reduction, the solution of 661 μg of tri(2-carboxyethyl)phosphine- hydrochloride in 236 μl 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 ΝAP-5 column at a concentration of 450 μl of AP39r and 50 μl 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
(1 S,3S,7S(3RS), 1 OR, 11 S, 12S, 16R)-[3-(3-(AP39r)-Sulfanyl-2,5-dioxo-pyrrolidin-l - yl)-propyl]-carbamic acid-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-yl ester 22.5 μl of a 1.38 mmol solution of effector-linker conjugate A in DMSO, prepared according to Example EL2, is added to 400 μl of the solution, prepared according to Example ELEla, of the reduced antibody fragment, mixed with 77.5 μl of PBS and incubated at 25°C for 1 hour. Desalination is done with a pre-equilibrated NAP5 column at a concentration of 500 μl of the reaction solution. After elution with PBS, the solution of the title compound is isolated The dilution factor relative to the antibody fragment is approximately 2.5. m/z (Calc): 26203.1 m/z (exp.): 26218 ± 20
Example ELE2
(lS,3S,7S(3RS),10R,HS,12S,16R)-[5-(3-(AP39r)-Sulfanyl-2,5-dioxo-pyrrolidin-l- yl)-pentyl]-carbamic acid-10-allyl-ll-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 Analogously to Example ELE1 , the antibody fragment that is reduced according to Example ELE la is reacted with effector-linker conjugate A that is prepared according to Example EL4, and the solution of the title compound is isolated. The dilution factor relative to the antibody fragment is approximately 2.5. m/z (Calc): 26231.2 m z (exp.): 26236 ± 20
Example ELE3
(1 S,3 S,7S(3RS), 1 OR, 11 S, 12S, 16R)-[10-(3-(AP39r)-Sulfanyl-2,5-dioxo-pyrrolidin-l- yl)-decyl] -carbamic acid- 10-allyl- 11 -hydroxy-8 ,8 , 12,16-tetramethy 1-3 -(2-methyl- benzothiazol-5-yl)-5,9-dioxo-4, 17-dioxabicyclo[l 4.1.0]heptadec-7-yl ester Analogously to Example ELE1 , the antibody fragment that is reduced according to Example ELE la is reacted with effector-linker conjugate A that is prepared according to Example EL6, and the solution of the title compound is isolated. The dilution factor relative to the antibody fragment is approximately 2.5. m/z (Calc): 26301.4 m z (exp.): 26303 ± 20
Example ELE4
(1 S,3S,7S, 1 OR, 11 S(3RS), 12S, 16R)-[3-(3-(AP39r)-Sulfanyl-2,5-dioxo-pyrrolidin-l - yl)-propyl] -carbamic acid- 10-allyl-7-hydroxy-8 ,8 , 12,16-tetramethy 1-3 -(2-methyl- benzothiazol-5-yl)-5,9-dioxo-4, 17-dioxabicyclo[l 4.1.0]heptadec-l 1 -yl ester 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 EL8, and the solution of the title compound is isolated. The dilution factor relative to the antibody fragment is approximately 2.5. m/z (Calc): 26203.2 m/z (exp.): 26206 ± 20
Example ELE5
(lS,3S,7S,10R,HS(3RS),12S,16R)-[5-(3-(AP39r)-Sulfanyl-2,5-dioxo-pyrrolidin-l- yl)-pentyl]-carbamic acid- 10-allyl-7-hydroxy-8,8, 12, 16-tetramethyl-3-(2-methyl- benzothiazol-5-yl)-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-ll-yl ester Analogously to Example ELE1, the antibody fragment that is reduced according to Example ELE la is reacted with effector-linker conjugate A that is prepared according to Example EL 10, and the solution of the title compound is isolated. The dilution factor relative to the antibody fragment is approximately 2.5. m/z (Calc): 26231.2 m/z (exp.): 26225 ± 20
Example ELE6
(lS,3S(E),7S,10R,HS,12S,16R)-[3-(3-(AP39r)-Sulfanyl-2,5-dioxo-pyrrolidin-l-yl)- propyl]-carbamic acid-7-[3-(2,5-dioxo-2,5-dihydro-pyrrol-l-yl)-propylcarbamoyloxy]-
8,8,10,12,16-ρentamethyl-3-[l-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-5,9-dioxo-
4, 17-dioxa-bicyclo[l 4.1.0]heptadec-l 1 -yl ester (A) and
(lS,3S(E),7S,10R,HS,12S,16R)-[3-(3-(AP39r)-Sulfanyl-2,5-dioxo-pyrrolidin-l-yl)- propylj-carbamic acid-1 l-[3-(2,5-dioxo-2,5-dihydro-pyrrol-l-yl)- propylcarbamoyloxy] -8, 8, 10,12,16-pentamethyl-3 - [ 1 -methyl-2-(2-methyl-thiazol-4- yl)-vinyl]-5,9-dioxo-4, 17-dioxa-bicyclo[ 14.1.0]heptadec-7-yl ester (B)
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 ELE7
(lS,3S(E),7S,10R,HS,12S,16R)-N-[l-({4-[2-(7,ll-Dihydroxy-8,8,10,12,16- pentamethyl-5,9-dioxo-4, 17-dioxa-bicyclo[14.1.0]heptadec-3-yl)-propenyl]-thiazol-2- ylmethyl}-carbamoyl)-ethyl]-3-(AP39r)-disulfanyl-N-methyl-propionamide
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 ELE8
(lS,3S(E),7S,10R,llS,12S,16R)-2-[Methyl-(3-(AP39r)-disulfanyl-propionyl)-amino]- propionic acid-4-[2-(7, 11 -dihydroxy-8,8, 10, 12, 16-pentamethyl-5,9-dioxo-4, 17-dioxa- bicyclo[14.1.0]heptadec-3-yl)-propenyl]-thiazol-2-ylmethyl ester
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 ELE9
(1S,3S,7S,10R,1 lS,12S,16R)-Carbonic acid- 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-yl ester 4-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-l-yl)- phenyl ester 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 3, and the solution of the title compound is isolated. The dilution factor relative to the antibody fragment is approximately 2.5. m/z (Calc): 26238 m/z (exp.): 26224 ± 20
Example ELE 10
(1 S,3S,7S,10R,1 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-ll-yl ester 4-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-l-yl)-phenyl ester 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 5, and the solution of the title compound is isolated. The dilution factor relative to the antibody fragment is approximately 2.5. m/z (Calc): 26238 m z (exp.): 26243 ± 20
Example ELEl 1
4-(3-(AP39r)-Sulfanyl-2,5-dioxo-pyrrolidin-l-yl)-butanoic acid 4-(lS,3S,7S,10R,l IS, 12S, 16R)-[10-allyl- 11 -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-nitro- phenyl ester
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 ELE 12 4-(3-(AP39r)-Sulfanyl-2,5-dioxo-pyrrolidin-l-yl)-butanoic acid 4-
(lS,3S,7S,10R,llS,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.Ojheptadec- 11- yloxycarbonyloxymethyl] -2-nitro-phenyl ester
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 ELE 13
6-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-l-yl)-hexanoic acid 4- (1S,3S,7S,10R,11S,12S, 16R)-[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- yloxycarbonyloxymethyl]-2-nitro-phenyl ester
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 ELE14
1 l-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-l-yl)-undecanoic acid 4-
(1S,3S,7S,10R,11S,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]-2-nitro-phenyl ester
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 ELE 15
6-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-l-yl)-hexanoic acid 4-
(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 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. m/z (Calc.) : 26411 m/z (exp.): 26398 ± 20 m/z (Calc.) : 25673 m z (exp.): 25665 ± 20 (6-(3-(AP39r)-sulfanyl-2,5-dioxo- pyrrolidin-l-yl)-hexanoic acid fragment)
Example ELE 16 1 l-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-l-yl)-undecanoic acid 4- (1S,3S,7S,10R,11S,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- 11- yloxycarbonyloxymethyl] -2-nitro-phenyl ester 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 ELE 17
4-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-l-yl)-butanoic acid 4- (1S,3S,7S,10R,11S,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
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 ELE 18 6-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-l-yl)-hexanoic acid 4-
(1S,3S,7S,10R,11S,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
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
1 l-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-l-yl)-undecanoic acid 4-
(1S,3S,7S,10R,11S,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] -phenyl ester
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 ELE20
4-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-l-yl)-butanoic acid 4- (1S,3S,7S,10R,11S,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- 11- yloxycarbonyloxymethyl] -2-nitro-phenyl ester
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 ELE21 6-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-l-yl)-hexanoic acid 4-
(1S,3S,7S,10R,11S,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] -phenyl ester
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
1 l-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-l-yl)-undecanoic acid 4-
(1S,3S,7S,10R,11S,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] -phenyl ester
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 ELE23
4-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-l-yl)-butanoic acid 4- (1S,3S,7S,10R,11S,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]-2-chloro-phenyl ester
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 ELE24
6-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-l-yl)-hexanoic acid 4-
(1S,3S,7S,10R,11S,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]-2-chloro-phenyl ester
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 ELE25
1 l-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-l-yl)-undecanoic acid 4- (1S,3S,7S,10R,11S,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] -2-chlor-phenyl ester 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 EL47 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.): 26463 ± 20
Example ELE26
4-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-l-yl)-butanoic acid 4- (1S,3S,7S,10R,11S,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- 11- yloxycarbonyloxymethyl]-2-chloro-phenyl ester
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 ELE27
6-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-l-yl)-hexanoic acid 4- (1S,3S,7S,10R,11S,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- yloxycarbonyloxymethyi] -2-chlor-phenyl ester
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 ELE28
1 l-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-l-yl)-undecanoic acid 4-
(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 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 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 ELE29
(1S,3S,7S,10R,1 lS,12S,16R)-Carbonic acid 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-yl ester 4-[4-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-l- yl)-butyrylamino]-3-nitro-benzyl ester
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 ELE30
(1S,3S,7S,10R,11S,12S,16R)-Carbonic acid 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-yl ester 4-[6-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-l- yl)-hexanoylamino]-3-nitro-benzyl ester
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 ELE31
(1S,3S,7S,10R,1 lS,12S,16R)-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]heρtadec-7-yl ester 4-[l l-(3-(AP39r)-sulfanyl-2,5-dioxo-ρyrrolidin-l- yl)-undecanoylamino] -3 -nitro-benzyl ester 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 EL59 and the solution of the title compound is isolated. The dilution factor relative to the antibody fragment is approximately 2.5. m/z (Calc.) : 26436 m/z (exp.): ± 20
Example ELE32
(1S,3S,7S,10R,1 lS,12S,16R)-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-7-yl ester 6-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-l-yl)- hexyl ester
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
Example ELE33
4-(3-(2H8-Ab)x-sulfanyl-2,5-dioxo-pyrrolidin-l-yl)-butanoic acid 4- (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-nitro-phenyl ester
100 μl of a solution of the thionylated antibody prepared according to Example ELE33a (about 3 nmol, about 6 thiol groups) are mixed with 42.3 μl of a 1.1 mM solution of the effector-linker conjugate A prepared according to Example EL25 in PBS, and the mixture is incubated at 23 °C for 1 hour. Desalination is performed by using a pre-equilibrated NAP5 column with a loading of 150 μl of the reaction solution. After elution with PBS, the solution of the title compound is isolated. The loading factor x of antibody 2H8-A in relation to effector-linker is about 1 :4 to 1 :5.
Example ELE33a
Thionylation of a complete immunoglobuline (IgG), e.g., the 2H8 antibody For the introduction of thionyl groups an amine-free solution of the 2H8 antibody in phosphate buffer having a concentration in the range of about 1-10 mg/ml at a pH of 7.2 is mixed with the 10- to 100-fold excess of 2-iminothiolane and is allowed to react for 1 hour at 23 °C. The number of the introduced thiol groups is 1 to about 15 depending on the excess of reagent.

Claims

Claims:
1. Effector conjugate of general formula (I):
Figure imgf000114_0001
in which
R a, R1^, independently of one another, are hydrogen, Cχ-Cχo alkyl, aryl, aralkyl, or together a XCH2)m §rouP» m which m is 2 to 5, R2a5 R2b5 independently of one another, are hydrogen, C \ -C x Q alkyl, aryl, aralkyl, or together a -(CH2)n group, in which n is 2 to 5, or C2-Cχo alkenyl, or C2-C10 alkynyl, R3 is hydrogen, Cχ-Cχo alkyl, aryl or aralkyl, and R^a, R b} independently of one another, are hydrogen, Cχ-Cχo alkyl, aryl, aralkyl, or together a -(CH2)p group, in which p is 2 to 5,
R5 is hydrogen, Cχ-Cιo alkyl, aryl, aralkyl, CO2H, CO2alkyl, CH2OH, CH2Oalkyl, CH2Oacyl, CN, CH2NH2, CH2N(alkyl, acyl)1 2, or CH2Hal, Hal is a halogen atom, R6, R7 i 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,
D-E is a group H2C-CH , HC=CH, C≡C, CH(OH)-CH(OH), CH(OH)-CH2,
O CH2-CH(OH), HC_CH , O-CH2, or, if G represents a CH2 group, D-E is
CH2-O, W is a group C(=X)R^, or a bicyclic or tricyclic aromatic or heteroaromatic radical, L- is hydrogen, or, if a radical in W contains a hydroxyl group, forms a group O-L^ with the latter, or, if a radical in W contains an amino group, forms a group NR25-L4 with the latter, R25 is hydrogen or C \ -C \ Q alkyl,
X is an oxygen atom, or two OR^O groups, or a C2-C1 ø alkylenedioxy group that may be straight or branched, or H/OR^, or a CRIORI 1 group, R8 is hydrogen, Cχ-Cχo alkyl, aryl, aralkyl, halogen or CN, and R9 is hydrogen or a protective group PG^,
RIO, Rl 1, in each 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/0R12, Rl2 can represent hydrogen or a protective group PG A- Y can represent a group O-C(=O), O-CH2, CH2-C(=O), NR21 -C(=O) or
NR21-SO2, R20 can represent C \ -C20 alkyl, R2 can represent a hydrogen atom or C \ -C \ Q alkyl, PG^, PGY, and PG^ can represent a protective group PG, and
L , L2, and L^, independently of one another, can represent hydrogen, a group
C(=O)Cl, a group C(=S)C1, a group PG^ or a linker of general formula
(III) or (IN); provided that at least one substituent L1, L2 or L4 represents a linker of general formula (III) or (IN); the linker of general formula (III) has the following structure,
Figure imgf000116_0001
h
T can represent oxygen or sulfur, U can represent oxygen, CHR 2, CHR22-ΝR 3-C(=O)-,
O-C(=O)-CHR 2-NR 3-C(=O)-, O-C(=O)-CHR2 -NR23-C(=S , CHR22-NR23-C(=S)- or NR 4a, o can represent 0 to 15,
N can represent a bond, aryl, a group
Figure imgf000116_0002
or a group NR24b-C(=S)-O-(CH2)s-^^ _
s can represent 0 to 4,
Q can represent a bond, O-C(=O)-NR24c, O-C(=S)-NR2 c,
Figure imgf000117_0001
R22 can represent hydrogen, C \ -C j Q alkyl, aryl or aralkyl, R23 can represent hydrogen or C \ -C \ Q alkyl,
R 4 5 R24bs and R24C 5 independently of one another, can represent hydrogen
or Cχ-Cχo alkyl, q can represent 0 to 15,
FGl can represent Cχ-Cιo alkyl-S3 ,
Figure imgf000117_0002
O //
-iJ
. or CO2H; and the linker of general formula (IN) has the following structure,
Figure imgf000117_0003
in which
T can represent oxygen or sulfur,
W1, W2 are the same or different and can represent oxygen or ΝR2 o can represent 0 to 5, R24a can represent hydrogen or Q-CJO alkyl,
R27 can represent halogen, CN, NO2, CO2R28, or OR28,
R28 can represent hydrogen, C1-C10 alkyl, aryl or aralkyl, q can represent 0 to 5,
U can represent oxygen, CHR22, CHR22-NR23-C(=O)-,
CHR22-NR23-C(=S)- or d- -o alkyl,
R22 can represent hydrogen, C \ -C \ Q alkyl, aryl or aralkyl,
R23 can represent hydrogen or C \ -C \ Q alkyl, r can represent 0 to 20, FG1 can represent d-Cι0 alkyl-S3,
Figure imgf000118_0001
as a single isomer or a mixture of different isomers and/or as a pharmaceutically acceptable salt thereof.
2. Effector conjugate according to claim 1, wherein:
A- Y represents O-C(=O) or NR21 -C(=O), D-E represents an H2C-CH2 group, G represents a CH2 group, Z represents an oxygen atom, Rl a, Rl b in each case represent C \ -C \ Q alkyl or together a ~(CH2) group with p equal to 2 or 3 or 4, R2a, R2b, independently of one another, represent hydrogen, Cχ-Cχo alkyl, C2-Cl0 alkenyl, or C2-C10 alkynyl, R3 represents hydrogen,
R4a, R4D, independently of one another, represent hydrogen or Cχ-Cχo alkyl;
R5 represents hydrogen, or C1-C4 alkyl or CH2OH or CH2NH2 or CH2N(alkyl, acyl)^ or CH2Hal, R6 and R^ together represent an additional bond or together an NH group, or together an N-alkyl group, or together a CH2 group, or together an oxygen atom,
W represents a group C(=X)R^ or a 2-methylbenzothiazol-5-yl radical or a 2-methylbenzoxazol-5-yl radical or a quinolin-7-yl radical or a 2-aminomethylbenzothiazol-5-yl radical or a
2-hydroxymethylbenzothiazol-5-yl radical or a 2-aminomethyl- benzoxazol-5-yl radical or a 2-hydroxymethylbenzoxazol-5-yl radical,
X represents a CR! ORI 1 group,
R represents hydrogen or C1-C4 alkyl or a fluorine atom or a chlorine atom or a bromine atom,
RIO/RI represent hydrogen/2-mefhylthiazol-4-yl or hydrogen/2-pyridyl or hydrogen/2-methyloxazol-4-yl or hydrogen/2-aminomethylthiazol-4-yl or hydrogen/2-aminomethyloxazol-4-yl or hydrogen/2- hydroxymethylthiazol-4-yl or hydrogen/2-hydroxymethyloxazol-4-yl.
3. Effector conjugate according to claim 1 or 2, wherein the effector element is selected from the group that consists of:
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[l- methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione; (4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4- yl)-l-methyl-vinyl]-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S, 13Z, 16S(E))- 16-[2-(2-Aminomethyl-thiazol-4-yl)-l -methyl- vinyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione; (lS,3S(E),7S,10R,llS,12S,16R)-7,ll-Dihydroxy-8,8,10,12,16-pentamethyl-3-
[1 -methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-4, 17-dioxa-bicyclo[l 4.1.0]heptadecane- 5,9-dione;
(lS,3S(E),7S,10R,llS,12S,16R)-7,ll-Dihydroxy-3-[2-(2-hydroxymethyl- thiazol-4-yl)- 1 -methyl-vinyl]-8,8, 10, 12, 16-pentamethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione;
(lS,3S(E),7S,10R,llS,12S,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-l-methyl- vinyl]-7, 11 -dihydroxy-8,8, 10, 12, 16-pentamethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[l- methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4- yl)-l -mefhyl-vinyl]-7-ethyl-5,5,9, 13 -tetramethyl-oxacyclohexadec- 13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-Aminomethyl-thiazol-4-yl)-l-methyl- vinyl]-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione; (lS,3S(E),7S,10R,HS,12S,16R)-7,l l-Dihydroxy-10-ethyl-8,8,12,16- tetramethyl-3 -[ 1 -methyl-2-(2-mefhyl-thiazol-4-yl)-vinyl] -4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione;
(1 S,3 S(E),7S,1 OR, 11 S, 12S, 16R)-7, 11 -Dihydroxy-3-[2-(2-hydroxymethyl- thiazol-4-yl)- 1 -methyl-vinyl]- 10-ethyl-8,8, 12,16-tetramethyl-4, 17-dioxa- bicyclo[l 4.1.0]hepta-decane-5 ,9-dione; (lS,3S(E),7S,10R,l lS,12S,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-l-methyl- vinyl]-7,ll-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa- bicyclo[14.1.0]hepta-decane-5,9-dione;
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[l- fluoro-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z, 16S(Z))-4,8-Dihydroxy-l 6-[2-(2-hydroxymethyl-thiazol-4- yl)-l-fluoro-vinyl]-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-thiazol-4-yl)-l-fluoro- vinyl]-4,8-dihydroxy-5,5,7,9, 13 -pentamethyl-oxacyclohexadec- 13-ene-2,6-dione; (1S,3S(Z),7S,10R,11S,12S,16R)-7,11 -Dihydroxy-8,8, 10, 12,16-pentamethyl-3-
[ 1 -fluoro-2-(2-methyl-thiazol-4-yl)-vinyl]-4, 17-dioxa-bicyclo [14.1.0]heptadecane-5,9- dione;
(1 S,3 S(Z),7S, 1 OR, 11 S, 12S, 16R)-7, 11 -Dihydroxy-3-[2-(2-hydroxymethyl- thiazol-4-yl)- 1 -fluoro-vinyl]-8,8, 10, 12, 16-pentamethyl-4, 17-dioxa- bicyclo [14.1.0]heptadecane-5 ,9-dione;
(1 S,3S(Z),7S,10R,11 S,12S,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-l-fluoro- vinyl] -7,11 -dihydroxy-8, 8 ,10,12,16-pentamethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[l- chloro-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S, 13Z, 16S(Z))-4,8-Dihydroxy-l 6-[2-(2-hydroxymethyl-thiazol-4- yl)- 1 -chloro-vinyl] -5,5,7,9,13 -pentamethyl-oxacyclohexadec- 13 -ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-thiazol-4-yl)-l-chloro- vinyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione; (lS,3S(Z),7S,10R,l lS,12S,16R)-7,l l-Dihydroxy-8,8,10,12,16-pentamethyl-3- [ 1 -chloro-2-(2-methyl-fhiazol-4-yl)- vinyl] -4, 17-dioxa-bicyclo [14.1.0]heptadecane-5 ,9- dione;
(1 S,3S(Z),7S, 1 OR, 11 S, 12S, 16R)-7, 11 -Dihydroxy-3-[2-(2-hydroxymethyl- thiazol-4-yl)- 1 -chloro-vinyl]-8,8, 10, 12, 16-pentamethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione;
(1 S,3S(Z),7S, 1 OR, 11 S, 12S,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-l -chloro- vinyl]-7, 11 -dihydroxy-8,8, 10, 12, 16-pentamethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione; (4S,7R,8S,9S, 13Z, 16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9, 13-tetramethyl-l 6-[l- fluoro-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4- yl)-l-fluoro-vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S, 13Z, 16S(Z))- 16-[2-(2- Aminomethyl-thiazol-4-yl)-l -fluoro- vinyl]-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;
(lS,3S(Z),7S,10R,HS,12S,16R)-7,ll-Dihydroxy-10-ethyl-8,8,12,16- tetramethyl-3 - [ 1 -fluoro-2-(2-methyl-thiazol-4-yl)-vinyl] -4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione;
(lS,3S(Z),7S,10R,l lS,12S,16R)-7,ll-Dihydroxy-3-[2-(2-hydroxymethyl- thiazol-4-yl)- 1 -fluoro-vinyl]- 10-ethyl-8,8, 12,16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]hepta-decane-5,9-dione;
(1 S,3 S(Z),7S, 1 OR, 11 S, 12S, 16R)-3 -[2-(2-Aminomethyl-thiazol-4-yl)- 1 -fluoro- vinyl]-7, 11 -dihydroxy- 10-ethyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]hepta-decane-5,9-dione; (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[l- chloro-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S, 13Z, 16S(Z))-4,8-Dihydroxy-l 6-[2-(2-hydroxymethyl-thiazol-4- yl)-l -chloro-vinyl]-7-ethyl-5,5,9, 13-tetramethyl-oxacyclohexadec- 13-ene-2,6-dione; (4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-thiazol-4-yl)-l-chloro- vinyl] -4, 8-dihydroxy-7-ethyl-5 ,5,9,13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione;
(lS,3S(Z),7S,10R,HS,12S,16R)-7,ll-Dihydroxy-10-ethyl-8,8,12,16- tetramethyl-3 - [ 1 -chloro-2-(2-methyl-thiazol-4-yl)-vinyl] -4, 17-dioxa- bicyclo[l 4.1.0]heptadecane-5,9-dione; (1S,3S(Z),7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-[2-(2-hydroxymethyl- thiazol-4-yl)- 1 -chloro-vinyl]- 10-ethyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]hepta-decane-5,9-dione;
(lS,3S(Z),7S,10R,l lS,12S,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-l-chloro- vinyl]-7, 11 -dihydroxy-10-ethyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[l- methyl-2-(2-pyridyl)-vinyl]-oxacyclohexadec- 13 -ene-2,6-dione;
(lS,3S(E),7S,10R,l lS,12S,16R)-7,l l-Dihydroxy-8,8,10,12,16-pentamethyl-3- [l-methyl-2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione; (4S,7R,8S,9S, 13Z, 16S(E))-4,8-Dihydroxy-7-ethyl-5,5,9,l 3-tetramethyl- 16-[l - methyl-2-(2-pyridyl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione;
(lS,3S(E),7S,10R,HS,12S,16R)-7,l l-Dihydroxy-10-ethyl-8,8,12,16- tetramethyl-3-[l-methyl-2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane- 5,9-dione; (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9, 13-pentamethyl-l 6-[l - fluoro-2-(2-pyridyl)-vinyl]-oxacyclohexadec- 13 -ene-2,6-dione;
(lS,3S(Z),7S,10R,llS,12S,16R)-7,ll-Dihydroxy-8,8,10,12,16-pentamethyl-3- [l-fluoro-2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione; (4S,7R,8S,9S,13Z, 16S(Z))-4,8-Dihydroxy-5,5,7,9, 13-pentamethyl-16-[l - chloro-2-(2-pyridyl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione;
(lS,3S(Z),7S,10R,llS,12S,16R)-7,U-Dihydroxy-8,8,10,12,16-pentamethyl-3- [l-chloro-2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[l- fluoro-2-(2-pyridyl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione;
(lS,3S(Z),7S,10R,HS,12S,16R)-7,ll-Dihydroxy-10-ethyl-8,8,12,16- tetramethyl-3-[l-fluoro-2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane- 5,9-dione;
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[l- chloro-2-(2-pyridyl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione;
(lS,3S(Z),7S,10R,llS,12S,16R)-7,ll-Dihydroxy-10-ethyl-8,8,12,16- tetramethyl-3-[l-chloro-2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane- 5,9-dione;
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[l- methyl-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4- yl)-l-methyl-vinyl]-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-Aminomethyl-oxazol-4-yl)-l-methyl- vinyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione; (lS,3S(E),7S,10R,llS,12S,16R)-7,l l-Dihydroxy-8,8,10,12,16-pentamethyl-3- [1 -methyl-2-(2-methyl-oxazol-4-yl)-vinyl]-4, 17-dioxa-bicyclo [14.1.Ojheptadecane- 5,9-dione;
(lS,3S(E),7S,10R,llS,12S,16R)-7,ll-Dihydroxy-3-[2-(2-hydroxymethyl- oxazol-4-yl)-l -methyl-vinyl]-8,8, 10, 12, 16-pentamethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione;
(lS,3S(E),7S,10R,llS,12S,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-l-methyl- vinyl]-7, 11 -dihydroxy-8,8, 10, 12, 16-pentamethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5 ,9-dione; (4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[l- methyl-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4- yl)-l-methyl-vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-Aminomethyl-oxazol-4-yl)-l-methyl- vinyl]-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramefhyl-oxacyclohexadec-13-ene-2,6-dione;
(lS,3S(E),7S,10R,HS,12S,16R)-7,ll-Dihydroxy-10-ethyl-8,8,12,16- tetramethyl-3-[l -methyl-2-(2-methyl-oxazol-4-yl)-vinyl]-4, 17-dioxa- bicyclo [14.1.0]heptadecane-5 ,9-dione;
(lS,3S(E),7S,10R,llS,12S,16R)-7,ll-Dihydroxy-3-[2-(2-hydroxymethyl- oxazol-4-yl)- 1 -methyl-vinyl] - 10-ethyl-8 ,8, 12,16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]hepta-decane-5 ,9-dione;
(lS,3S(E),7S,10R,llS,12S,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-l-methyl- vinyl]-7, 11 -dihydroxy- 10-ethyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14!.0]hepta-decane-5,9-dione; (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[l- fluoro-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4- yl)- 1 -fluoro-vinyl] -5,5,7,9,13 -pentamethyl-oxacyclohexadec- 13 -ene-2,6-dione; (4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-oxazol-4-yl)-l-fluoro- vinyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione;
(lS,3S(Z),7S,10R,llS,12S,16R)-7,ll-Dihydroxy-8,8,10,12,16-pentamethyl-3- [l-fluoro-2-(2-methyl-oxazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dione; (1S,3S(Z),7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-[2-(2-hydroxymethyl- oxazol-4-yl)-l-fluoro-vinyl]-8,8,10,12,16-pentamethyl-4,17-dioxa- bicyclo[14.1.0]heptadecane-5 ,9-dione;
(lS,3S(Z),7S,10R,llS,12S,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-l-fluoro- vinyl]-7,l 1 -dihydroxy-8,8,10, 12,16-pentamethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[l- chloro-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4- yl)-l-chloro-vinyl]-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione; (4S,7R,8S,9S, 13Z, 16S(Z))- 16-[2-(2-Aminomethyl-oxazol-4-yl)-l-chloro- vinyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione;
(lS,3S(Z),7S,10R,l lS,12S,16R)-7,ll-Dihydroxy-8,8,10,12,16-pentamethyl-3- [l-chloro-2-(2-methyl-oxazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dione; ( 1 S,3S(Z),7S, 1 OR, 11 S, 12S, 16R)-7, 1 l-Dihydroxy-3-[2-(2-hydroxymethyl- oxazol-4-yl)-l -chloro-vinyl]-8,8, 10, 12, 16-pentamethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione;
(lS,3S(Z),7S,10R,HS,12S,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-l-chloro- vinyl]-7,l l-dihydroxy-8,8,10,12,16-ρentamethyl-4,17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[l- fluoro-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4- yl)-l-fluoro-vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S, 13Z, 16S(Z))- 16-[2-(2-Aminomethyl-oxazol-4-yl)- 1 -fluoro- vinyl]-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;
(lS,3S(Z),7S,10R,HS,12S,16R)-7,ll-Dihydroxy-10-ethyl-8,8,12,16- tetramethyl-3 - [ 1 -fluoro-2-(2-methyl-oxazol-4-yl)-vinyl] -4, 17-dioxa- bicyclo[14.1.0]heptadecane-5 ,9-dione;
(1S,3S(Z),7S,10R,11 S,12S,16R)-7,1 l-Dihydroxy-3-[2-(2-hydroxymethyl- oxazol-4-yl)-l -fluoro-vinyl]- 10-ethyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]hepta-decane-5,9-dione;
(lS,3S(Z),7S,10R,l lS,12S,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-l-fluoro- vinyl]-7, 11 -dihydroxy- 10-ethyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]hepta-decane-5,9-dione;
(4S,7R,8S,9S, 13Z, 16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9, 13-tetramethyl-l 6-[l - chloro-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S, 13Z, 16S(Z))-4,8-Dihydroxy-l 6-[2-(2-hydroxymethyl-oxazol-4- yl)- 1 -chloro-vinyl]-7-efhyl-5,5,9, 13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione; (4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-oxazol-4-yl)-l-chloro- vinyl]-4,8-dihydroxy-7-ethyl-5,5,9, 13-tetramethyl-oxacyclohexadec- 13-ene-2,6-dione;
(lS,3S(Z),7S,10R,HS,12S,16R)-7,l l-Dihydroxy-10-ethyl-8,8,12,16- tetramethyl-3 - [ 1 -chloro-2-(2-methyl-oxazol-4-yl)-vinyl] -4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione;
(lS,3S(Z),7S,10R,l lS,12S,16R)-7,ll-Dihydroxy-3-[2-(2-hydroxymethyl- oxazol-4-yl)- 1 -cl loro-vinyl]- 10-ethyl-8,8, 12,16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]hepta-decane-5,9-dione;
(lS,3S(Z),7S,10R,HS,12S,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-l-chloro- vinyl]-7, 11 -dihydroxy- 10-ethyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]hepta-decane-5,9-dione;
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[2-(2- methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4- yl)-vinyl]-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-Aminomethyl-thiazol-4-yl)-vinyl]-4,8- dihydroxy-5,5,7,9, 13 -pentamethyl-oxacyclohexadec- 13-ene-2,6-dione;
(lS,3S(E),7S,10R,l lS,12S,16R)-7,l l-Dihydroxy-8,8,10,12,16-pentamethyl-3- [2-(2-methyl-thiazol-4-yl)-vinyl]-4, 17-dioxa-bicyclo [14.1.0]heptadecane-5,9-dione; (lS,3S(E),7S,10R,llS,12S,16R)-7,ll-Dihydroxy-3-[2-(2-hydroxymethyl- thiazol-4-yl)-vinyl]-8,8, 10, 12, 16-pentamethyl-4, 17-dioxa-bicyclo [14.1.Ojheptadecane- 5,9-dione;
(1 S,3S(E),7S, 1 OR, 11 S, 12S, 16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-vinyl]- 7, 11 -dihydroxy-8,8, 10, 12, 16-pentamethyl-4, 17-dioxa-bicyclo [14.1.0]heptadecane-5,9- dione; (4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[2-
(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4-
yl)-vinyl] -7-ethyl-5 ,5 ,9, 13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione; (4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-Aminomethyl-thiazol-4-yl)-vinyl]-4,8- dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione; (lS,3S(E),7S,10R,HS,12S,16R)-7,ll-Dihydroxy-10-ethyl-8,8,12,16- tetramethyl-3-[2-(2-methyl-thiazol-4-yl)-vinyl]-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione; (1S,3S(E),7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-[2-(2-hydroxymethyl- fhiazol-4-yl)-vinyl]- 10-ethyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo [14.1.0]heptadecane-5 ,9-dione;
(1 S,3S(E),7S, 1 OR, 11 S, 12S,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-vinyl]- 7, 11 -dihydroxy- 10-ethyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[2-(2- pyridyl)-vinyl]-oxacyclohexadec- 13 -ene-2,6-dione;
(lS,3S(E),7S,10R,llS,12S,16R)-7,ll-Dihydroxy-8,8,10,12,16-pentamethyl-3- [2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione; (4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[2-
(2-pyridyl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione;
(lS,3S(E),7S,10R,HS,12S,16R)-7,l l-Dihydroxy-10-ethyl-8,8,12,16- tetramethyl-3 - [2-(2-pyridyl)- vinyl] -4, 17-dioxa-bicyclo [14.1.0]heptadecane-5 ,9-dione; (4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy-5,5,7,9, 13-pentamethyl-l 6-(2-methyl- benzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione; (4S,7R,8S,9S, 13Z,16S)-4,8-Dihydroxy- 16-(2-hydroxymethyl-benzothiazol-5- yl)-5 ,5,7,9,13 -pentamethyl-oxacyclohexadec- 13 -ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy- 5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione; (1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-8,8,10,12,16-pentamethyl-3-(2- methyl-benzothiazol-5-yl)-4,l 7-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione;
(1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-(2-hydroxymethyl- benzothiazol-5-yl)-8,8, 10,12, 16-pentamethyl-4, 17-dioxa-bicyclo[14.1.Ojheptadecane- 5,9-dione; (1S,3S,7S,10R,1 lS,12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,l 1- dihydroxy-8,8, 10, 12, 16-pentamethyl-4, 17-dioxa-bicyclo [14.1.0]heptadecane-5 ,9- dione;
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-(2- methyl-benzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione; (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5- yl)-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy- 7-ethyl-5,5,9, 13 -tetramethyl-oxacyclohexadec- 13-ene-2,6-dione;
(lS,3S,7S,10R,llS,12S,16R)-7,ll-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl- 3-(2-methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione;
(lS,3S,7S,10R,l lS,12S,16R)-7,ll-Dihydroxy-3-(2-hydroxymethyl- benzothiazol-5-yl)- 10-ethyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione; (lS,3S,7S,10R,HS,12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,l l- dihydroxy- 10-ethyl-8,8, 12, 16-tetramethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dione;
(4S,7R,8S,9S, 13Z,16S)-4,8-Dihydroxy-7-propyl-5,5,9, 13-tetramethyl-l 6-(2- methyl-benzothiazol-5-yl)-oxacyclohexadec- 13-ene-2,6-dione;
(4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy-l 6-(2-hydroxymethyl-benzothiazol-5- yl)-7-propyl-5 ,5,9,13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy- 7-propyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione; (lS,3S,7S,10R,HS,12S,16R)-7,l l-Dihydroxy-10-propyl-8,8,12,16- tetramethyl-3-(2-methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane- 5,9-dione;
(1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-(2-hydroxymethyl- benzothiazol-5-yl)- 10-propyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione;
(1 S,3S,7S, 1 OR, 11 S, 12S, 16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7, 11 - dihydroxy- 10-propyl-8,8, 12, 16-tetramethyl-4, 17-dioxa-bicyclo [14.1.0]heptadecane- 5,9-dione;
(4S,7R,8S,9S, 13Z,16S)-4,8-Dihydroxy-7-butyl-5,5,9, 13-tetramethyl-l 6-(2- methyl-benzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5- yl)-7-butyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy- 7-butyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione; (lS,3S,7S,10R,llS,12S,16R)-7,l l-Dihydroxy-10-butyl-8,8,12,16-tetramethyl- 3-(2-methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione;
(lS,3S,7S,10R,llS,12S,16R)-7,ll-Dihydroxy-3-(2-hydroxymethyl- benzothiazol-5-yl)- 10-butyl-8,8, 12,16-tetramethyl-4, 17-dioxa- bicyclo[l 4.1.0]heptadecane-5,9-dione;
(lS,3S,7S,10R,llS,12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,ll- dihydroxy- 10-butyl-8 , 8, 12,16-tetramethyl-4, 17-dioxa-bicyclo [14.1.0]heptadecane-5 ,9- dione;
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-allyl-5,5,9,13-tetramethyl-16-(2- methyl-benzothiazol-5-yl)-oxacyclohexadec-l 3-ene-2,6-dione;
(4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy- 16-(2-hydroxymethyl-benzothiazol-5- yl)-7-allyl-5 ,5,9,13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione;
(4S,7R,8S,9S, 13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy- 7-allyl-5,5,9, 13-tetramethyl-oxacyclohexadec- 13-ene-2,6-dione; (lS,3S,7S,10R,l lS,12S,16R)-7,ll-Dihydroxy-10-allyl-8,8,12,16-tetramethyl-
3-(2-methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione;
(1 S,3S,7S, 10R,11 S, 12S,16R)-7, 11 -Dihydroxy-3-(2-hydroxymethyl- benzothiazol-5-yl)-l 0-allyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione; (1S,3S,7S,10R,1 lS,12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,l 1- dihydroxy-10-allyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dione;
(4S,7R,8S,9S, 13Z,16S)-4,8-Dihydroxy-7-prop-2-inyl-5,5,9, 13-tetramethyl- 16- (2-methyl-benzothiazol-5-yl)-oxacyclohexadec- 13 -ene-2,6-dione; (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5- yl)-7-prop-2-inyl-5 ,5,9,13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione;
(4S,7R,8S,9S, 13Z, 16S)- 16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy- 7-prop-2-inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione; (1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-10-prop-2-inyl-8,8,12,16- tetramethyl-3-(2-methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane- 5,9-dione;
(lS,3S,7S,10R,l lS,12S,16R)-7,ll-Dihydroxy-3-(2-hydroxymethyl- benzothiazol-5-yl)- 10-prop-2-inyl-8,8, 12,16-tetramethyl-4, 17-dioxa- bicyclo[ 14.1.0]heptadecane-5,9-dione;
(1 S,3 S,7S, 1 OR, 11 S, 12S, 16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,l 1- dihydroxy- 10-prop-2-inyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-but-3-enyl-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5- yl)-7-but-3-enyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy- 7-but-3-enyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione; (lS,3S,7S,10R,HS,12S,16R)-7,l l-Dihydroxy-10-but-3-enyl-8,8,12,16- tetramethyl-3-(2-methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane- 5,9-dione;
(1 S,3 S,7S,1 OR, 11 S, 12S, 16R)-7, 11 -Dihydroxy-3-(2-hydroxymethyl- benzothiazol-5-yl)- 10-but-3-enyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione; (lS,3S,7S,10R,llS,12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,ll-
dihydroxy- 10-but-3-enyl-8,8, 12,16-tetramethyl-4, 17-dioxa- bicyclo [14.1.0]heptadecane-5 ,9-dione;
(4S,7R,8S,9S,13Z, 16S)-4,8-Dihydroxy-7-but-3-inyl-5,5,9, 13-tetramethyl- 16- (2-methyl-benzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5- yl)-7-but-3 -inyl-5 ,5,9,13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy- 7-but-3 -inyl-5 ,5,9,13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione; (lS,3S,7S,10R,HS,12S,16R)-7,l l-Dihydroxy-10-but-3-inyl-8,8,12,16- tetramethyl-3 -(2-methyl-benzothiazol-5 -yl)-4, 17-dioxa-bicyclo [14.1.Ojheptadecane- 5,9-dione;
(1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-(2-hydroxymethyl- benzothiazol-5-yl)- 10-but-3-inyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione;
(lS,3S,7S,10R,HS,12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,ll- dihydroxy- 10-but-3-inyl-8,8, 12,16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy-5,5,7,9, 13-pentamethyl-l 6-(2-methyl- benzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5- yl)-5 ,5,7,9, 13 -pentamethyl-oxacyclohexadec- 13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy- 5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione; (lS,3S,7S,10R,l lS,12S,16R)-7,ll-Dihydroxy-8,8,10,12,16-pentamethyl-3-(2- methyl-benzoxazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione;
(1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-(2-hydroxymethyl- benzoxazol-5-yl)-8,8, 10, 12,16-pentamethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane- 5,9-dione;
(1 S,3 S,7S, 1 OR, 11 S, 12S, 16R)-3-(2- Aminpmethyl-benzoxazol-5-yl)-7, 11 - dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dione;
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-(2- methyl-benzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy- 16-(2-hydroxymethyl-benzoxazol-5- yl)-7-ethyl-5 ,5 ,9, 13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy- 7-ethyl-5,5,9, 13 -tetramethyl-oxacyclohexadec- 13-ene-2,6-dione; (1S,3S,7S,10R,11S,12S,16R)-7,11 -Dihydroxy- 10-ethyl-8,8, 12,16-tetramethyl-
3 -(2-methyl-benzoxazol-5 -yl)-4, 17-dioxa-bicyclo [14.1.0]heptadecane-5 ,9-dione;
(1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-(2-hydroxymethyl- benzoxazol-5-yl)- 10-ethyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione; (1S,3S,7S,10R,1 lS,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,l 1- dihydroxy- 10-ethyl-8,8, 12,16-tetramethyl-4, 17-dioxa-bicyclo [14.1.0]heptadecane-5,9- dione;
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-propyl-5,5,9,13-tetramethyl-16-(2- methyl-benzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione; (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5- yl)-7-propyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S, 13Z, 16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy- 7-propyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione; (lS,3S,7S,10R,HS,12S,16R)-7,ll-Dihydroxy-10-propyl-8,8,12,16- tetramethyl-3-(2-methyl-benzoxazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-
dione;
(1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-(2-hydroxymethyl- benzoxazol-5-yl)- 10-propyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione;
(lS,3S,7S,10R,l lS,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,ll- dihydroxy- 10-propyl-8,8, 12, 16-tetramethyl-4, 17-dioxa-bicyclo [ 14.1.Ojheptadecane- 5,9-dione;
(4S,7R,8S,9S,13Z, 16S)-4,8-Dihydroxy-7-butyl-5,5,9,l 3-tetramethyl- 16-(2- methyl-benzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5- yl)-7-butyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S, 13Z, 16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy- 7-butyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione; (lS,3S,7S,10R,llS,12S,16R)-7,ll-Dihydroxy-10-butyl-8,8,12,16-tetramethyl-
3 -(2-methyl-benzoxazol-5-yl)-4, 17-dioxa-bicyclo [ 14.1.0]heptadecane-5 ,9-dione;
(1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-(2-hydroxymethyl- benzoxazol-5-yl)- 10-butyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione; (lS,3S,7S,10R,llS,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,l l- dihydroxy-10-butyl-8,8, 12, 16-tetramethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dione;
(4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy-7-allyl-5,5,9, 13 -tetramethyl- 16-(2- methyl-benzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy- 16-(2-hydroxymethyl-benzoxazol-5- yl)-7-allyl-5 ,5 ,9, 13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy- 7-allyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione; (1S,3S,7S,10R,11S,12S,16R)-7,11 -Dihydroxy- 10-allyl-8,8, 12,16-tetramethyl-
3-(2-methyl-benzoxazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione;
(1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-(2-hydroxymethyl- benzoxazol-5-yl)- 10-allyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione; (1S,3S,7S,10R,1 lS,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,l 1- dihydroxy-10-allyl-8,8,l 2, 16-tetramethyl-4, 17-dioxa-bicyclo[14.1.0]heptadecane-5,9- dione;
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-prop-2-inyl-5,5,9,13-tetramethyl-16- (2-methyl-benzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione; (4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy- 16-(2-hydroxymethyl-benzoxazol-5- yl)-7-prop-2-inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S, 13Z, 16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy- 7-prop-2-inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione; (lS,3S,7S,10R,HS,12S,16R)-7,l l-Dihydroxy-10-prop-2-inyl-8,8,12,16- tetramethyl-3-(2-methyl-benzoxazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-
dione;
(1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-(2-hydroxymethyl- benzoxazol-5-yl)- 10-prop-2-inyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione;
(lS,3S,7S,10R,llS,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,ll- dihydroxy- 10-prop-2-inyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5 ,9-dione; (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-but-3-enyl-5,5,9,13-tetramethyl-16-
(2-methyl-benzoxazol-5-yι)-oxacyclohexadec- 13 -ene-2,6-dione;
(4S,7R,8S,9S, 13Z, 16S)-4,8-Dihydroxy- 16-(2-hydroxymethyl-benzoxazol-5- yl)-7-but-3 -enyl-5 ,5 ,9, 13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy- 7-but-3 -enyl-5 ,5,9,13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione;
(lS,3S,7S,10R,llS,12S,16R)-7,ll-Dihydroxy-10-but-3-enyl-8,8,12,16- tetramethyl-3 -(2-methyl-benzoxazol-5 -yl)-4, 17-dioxa-bicyclo [14.1.0]heptadecane-5 ,9- dione;
(1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-(2-hydroxymethyl- benzoxazol-5-yl)- 10-but-3-enyl-8,8, 12,16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione;
(lS,3S,7S,10R,llS,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,l l- dihydroxy- 10-but-3-enyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5 ,9-dione; (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-but-3-inyl-5,5,9,13-tetramethyl-16-
(2-methyl-benzoxazol-5-yl)-oxacyclohexadec- 13 -ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5-
yι)-7-but-3 -inyl-5 ,5,9,13 -tetramethyl-oxacyclohexadec- 13 -ene-2,6-dione; (4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy-
7-but-3-inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;
(lS,3S,7S,10R,HS,12S,16R)-7,ll-Dihydroxy-10-but-3-inyl-8,8,12,16- tetramethyl-3-(2-methyl-benzoxazol-5-yl)-4,l 7-dioxa-bicyclo[14.1.0]heptadecane-5,9- dione; (1S,3S,7S,10R,11S,12S,16R)-7,1 l-Dihydroxy-3-(2-hydroxymethyl- benzoxazol-5-yl)-10-but-3-inyl-8,8,12,16-tetramethyl-4,17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione;
(1 S,3S,7S,10R,1 lS,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,l 1- dihydroxy- 10-but-3-inyl-8,8, 12, 16-tetramethyl-4, 17-dioxa- bicyclo[14.1.0]heptadecane-5,9-dione, wherein the hydrogen atoms in the above-mentioned effector elements are replaced in the positions indicated in formula (I) by radicals L^L3.
4. Effector conjugate according to any one of claims 1-3, wherein the linker is selected from the group that consists of the compounds of general formula (III), wherein
N represents a bond or an aryl radical, o is zero, and
T is an oxygen atom.
5. Effector conjugate according to any one of claims 1-3, wherein the linker is selected from the group that consists of the compounds of general formula (III), wherein
N represents a bond or an aryl radical or a group
ΝR24b-C(=O)-O-(CH2)s--^~^ _ > o is 0 to 4, and
Q is a bond or a group
Figure imgf000140_0001
6. Effector conjugate according to claim 5, wherein V is a bond or a group
Figure imgf000140_0002
-O-C(=O)-NR24c— ^T^ Q is a bond or a group o is 0, 2 or 3, s is 1, and 5 T is an oxygen atom.
7. Effector conjugate according to any one of claims 1-3, wherein the linker is selected from the group that consists of compounds of general formula (IN), wherein o is 0 to 4, and 0 q is 0 to 3.
8. Effector conjugate according to claim 7, wherein o is 0, 2 or 3,
W1 is oxygen, q is O,
R 22 is hydrogen, d-C3 alkyl or aralkyl,
R )23 is hydrogen or d-C3 alkyl,
R24a is hydrogen or C j -C3 alkyl,
R27 is fluorine, chlorine, CN, NO2, CO2R28 or OR28,
R28 is hydrogen or Cι-C5 alkyl, and
U is oxygen, CHR22, or CHR22-NR23-C(=O)-.
9. Effector recognition unit conjugate of general formula (I),
Figure imgf000141_0001
wherein the substituents therein have the meanings that are mentioned in claim 1, but at least one group FG1 is replaced by a group FG2a or FG2b, wherein FG2a or FG2b can have the following meanings:
Figure imgf000142_0001
FG2b: -CONH-; and wherein a recognition unit is conjugated via a sulfur atom with the group FG2a or via an amide function with group FG2b; wherein the recognition unit is selected from the group that consists of peptides, soluble receptors, cytokines, lymphokines, aptamers, spiegelmers, recombinant proteins, new framework structures, monoclonal antibodies and fragments of monoclonal antibodies; as a single isomer or a mixture of different isomers and/or as a pharmaceutically acceptable salt thereof.
10. Effector recognition unit conjugate according to claim 9, wherein the conjugate contains more than one recognition unit, and wherein the recognition units are identical.
11. Effector recognition unit conjugate according to claim 9 or 10, wherein the recognition unit is an antibody, or an antigen-binding fragment thereof, which is specific for an antigen that is selected from the group that consists of the antigens that are cited in Table 1, as well as CD19, CD20, CD40, CD22, CD25, CD5, CD52, CD10, CD2, CD7, CD33, CD38, CD40, CD72, CD4, CD21, CD37, CD30, NCAM, CD31, ELAM, endoglin, NEGFRI/II, αvβ3, Tiel/2, TES23 (CD44ex6), phosphatidylserine, PSMA, NEGFR/NEGF complex and ED-B-fibronectin.
12. Linker of general formula (III1):
RG1 (CH2)-V— (CH2)q— FG1 |||lf
in which
RG1 is an O=C=N group or an S=C=N group, and o, V, q and FG1 have the meanings that are mentioned in claim 1 ; or linker of general formula (III2):
RG2 (CH2)-V— (CH2)q— FG1 |||2,
in which
RG2 is a Hal-C(=T)-CHR22 group, or a Hal-C(=T)-CHR 2-NR23-C(=T) group, or an R2(5-C(=O)-O-C(=T)-CHR22 group, or an R26-C(=O)-O-C(=T)-CHR22- NR23-C(=T) group, wherein R26 is Cχ-Cχo alkyl, aryl, or aralkyl, and o, V, q and FG1 have the meanings that are mentioned in claim 1 ; or linker of general formula (III3):
RG3 (CH2)— V— (CH2)q— FG1 |||3,
in which
RG3 is an OH group, or an NHR 4a group, or a COOH group, and o, V, q and
FG1 have the meanings that are mentioned in claim 1; but with the proviso that the compound l-(4-amino-phenyl)-pyrrole-2,5-dione is not included.
13. Linker of general formula (IN1):
Figure imgf000144_0001
in which RG1 is an O=€=Ν group or an S=C=N group, and o, q, r, W2, R27, U and FG1 have the meanings that are mentioned in claim 1 ; or linker of general formula (IN ):
Figure imgf000144_0002
in which
RG2 is a Hal-C(=T)-CHR22 group, or a Hal-C(=T)-CHR22-ΝR23-C(=T) group, or an R26-C(=O)-O-C(=T)-CHR22 group, or an R26-C(=O)-O-C(=T)-CHR22- NR23-C(=T) group, wherein R26 is Cι-C10 alkyl, aryl, or aralkyl, and R22, R23, T, o, q, r, W2, R27, U and FG1 have the meanings that are mentioned in claim 1 ; or linker of general formula (IN ):
Figure imgf000144_0003
in which RG3 is an OH group or an NHR24a gr0up or a COOH group, and R24, o, q, r, W2, R27, U and FG1 have the meanings that are mentioned in claim 1.
14. Linker according to claim 12, wherein V represents a bond or an aryl radical, o is equal to zero, and T is an oxygen atom.
15. Linker according to claim 12, wherein
V represents a bond or an aryl radical or a group
Figure imgf000145_0001
o is 0 to 4, and
-O-C(=O)-NR24c— T^ Q is a bond or a group
16. Linker according to claim 15, wherein
V is a bond or a group
Q i
Figure imgf000145_0002
s a bond or a group o is 0, 2 or 3, s is 1, and
T is an oxygen atom.
17. Linker according to claim 13, wherein o is 0 to 4, and q is 0 to 3.
18. Linker according to claim 17, wherein o is 0, 2 or 3,
W1 is oxygen, q is O,
00
R is hydrogen, d-C3 alkyl or aralkyl, R23 is hydrogen or d-C3 alkyl,
R24a is hydrogen or d-C3 alkyl, R27 is fluorine, chlorine, CN, NO2, CO2R28 or OR28, R is hydrogen, or d-C5 alkyl, and U is oxygen, CHR22, or CHR22-NR23-C(=O)-.
19. Method for the production of effector conjugates according to any one of claims 1-8, wherein a compound of general formula (I), wherein the substituents have the meanings that are mentioned in claim 1, but the condition that at least one substituent l , \X ox lβ represent a linker of general formula (III) or (IN) need not be met, and at least one substituent L^, L2 or L4 represents hydrogen, a group C(=O)Cl, or a group C(=S)C1, is reacted with a linker that is selected from the group that consists of a linker of general formula (III1), (III2), (III3), (IN1), (IN2) or (IN3), as described in claims 12 to 18.
20. Method for the production of effector recognition unit conjugates according to one of claims 9 to 11, wherein an effector conjugate according to any one of claims 1-8 is reacted with at least one recognition unit as defined in claims 9 and 11.
21. Use of a compound of general formula (I), wherein the substituents have the meanings that are mentioned in claim 1, but the condition that at least one substituent L , L2 or L4 represent a linker of general formula (III) or (IN) need not be met, and at least one substituent L^, L2 or L4 represents hydrogen, a group C(=O)Cl, or a group C(=S)C1, in a method according to claim 19.
22. Use of a compound of general formula (I) for the production of an effector recognition unit conjugate according to claims 9 to 11.
23. Use of a linker of general formula (III1), (III2), (III3), (IN1), (IN2) or (IN3) in a method according to claim 19.
24. Use of a linker of general formula (III1), (III2), (III3), (IN1), (IN2) or (IN3) for the production of an effector recognition unit conjugate according to any one of claims 9 to 11.
25. Use of a recognition unit, as defined in claim 9 or 11 , in a method according to claim 20.
26. Effector recognition unit conjugate according to any one of claims 9 to 11 for use as a medicament.
27. Effector recognition unit conjugate according to any one of claims 9 to 11 for use as a medicament for treating diseases that are associated with proliferative processes.
28. Effector recognition unit conjugate according to any one of claims 9 to 11 for use as a medicament for treating a disease that is selected from the group that consists of tumors, inflammatory diseases, neurodegenerative diseases, angiogenesis- associated diseases, multiple sclerosis, Alzheimer's disease, and rheumatoid arthritis.
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