DE10234975A1 - New effector conjugates of epithilones useful to treat e.g. diseases associated with proliferative processes, neurodegenerative diseases, multiple sclerosis, Alzheimer's disease and rheumatoid arthritis - Google Patents

New effector conjugates of epithilones useful to treat e.g. diseases associated with proliferative processes, neurodegenerative diseases, multiple sclerosis, Alzheimer's disease and rheumatoid arthritis Download PDF

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DE10234975A1
DE10234975A1 DE10234975A DE10234975A DE10234975A1 DE 10234975 A1 DE10234975 A1 DE 10234975A1 DE 10234975 A DE10234975 A DE 10234975A DE 10234975 A DE10234975 A DE 10234975A DE 10234975 A1 DE10234975 A1 DE 10234975A1
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Prior art keywords
dione
dihydroxy
tetramethyl
oxacyclohexadec
dioxa
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Markus Berger
Ulrich Klar
Gerhard Siemeister
Jörg WILLUDA
Andreas Menrad
Klaus Bosslet
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Bayer Pharma AG
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Schering AG
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Priority to DE10234975A priority Critical patent/DE10234975A1/en
Priority to ARP030102734A priority patent/AR040956A1/en
Priority to PE2003000756A priority patent/PE20040747A1/en
Priority to CNA038181118A priority patent/CN1812785A/en
Priority to US10/631,011 priority patent/US7129254B2/en
Priority to NZ537870A priority patent/NZ537870A/en
Priority to PL03374528A priority patent/PL374528A1/en
Priority to CA002492437A priority patent/CA2492437A1/en
Priority to IL16603903A priority patent/IL166039A0/en
Priority to TW092121014A priority patent/TW200404065A/en
Priority to PCT/EP2003/008483 priority patent/WO2004012735A2/en
Priority to EA200500223A priority patent/EA200500223A1/en
Priority to UY27915A priority patent/UY27915A1/en
Priority to JP2005506073A priority patent/JP2006505627A/en
Priority to YUP-2005/0082A priority patent/RS20050082A/en
Priority to MXPA05001282A priority patent/MXPA05001282A/en
Priority to BR0313043-6A priority patent/BR0313043A/en
Priority to KR1020057001569A priority patent/KR20050026033A/en
Priority to EP03743752A priority patent/EP1524979A2/en
Priority to AU2003253365A priority patent/AU2003253365A1/en
Publication of DE10234975A1 publication Critical patent/DE10234975A1/en
Priority to IS7708A priority patent/IS7708A/en
Priority to EC2005005626A priority patent/ECSP055626A/en
Priority to ZA200501648A priority patent/ZA200501648B/en
Priority to CO05017568A priority patent/CO5700741A2/en
Priority to NO20051038A priority patent/NO20051038L/en
Priority to HR20050186A priority patent/HRP20050186A2/en
Priority to US11/509,557 priority patent/US7335775B2/en
Priority to US12/000,258 priority patent/US20080166362A1/en
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Abstract

Effector conjugates of epithilones (I) as a single isomer or mixture of different isomer and/or their salts are new. Effector conjugates of epithilones of formula (I) as a single isomer or mixture of different isomer and/or their salts are new; R1a, R1b = H, 1-10C alkyl, aryl, aralkyl; or R1a+R1b = (CH2)m; either R2a, R2b = H, 1-10C alkyl, aryl, aralkyl; or R2a+R2b = (CH2)n; R3 = H, 1-10C alkyl, aryl or aralkyl; either R4a, R4b = H, 1-10C alkyl, aryl aralkyl; or R4a+R4b = (CH2)p; R5 = 1-10C alkyl, aryl, aralkyl, CO2H, CH2O alkyl, CH2O acyl, CN, CH2NH2, CH2N (alkyl, acyl)1,2 or CH2 Hal; Hal = halo; either R6, R7 = H; or R6+R7 = bond, O, NH, N alkyl or CH2; G = O or CH2; D-E = H2C-CH2, HC=CH, Ctriple bondC, CH(OH)-CH(OH), CH(OH)-CH2, CH2CH(OH), ethylene epoxide, OCH2; when G = CH2, D-E = CH2O; W = C(=X)R8, bicyclic or tricyclic aromatic or heteroaromatic; L3 = H; or when W = OH, L3 = OL4 or when W = amino, L3 = NR25L4; Z = O or H/OR12; A-Y = OC(=O), OCH2, CH2C(=O), NR21C(=O) or NR21SO2; L1, L2, L4 = H, C(=O)Cl, C(=S)Cl, PG-Y or a linker of formula (III) or IV; and m,n,p = 2-5. Provided that at least one of L1, L2 or L4 represents a linker of formula (III) or (IV). Full definitions are given in the DEFINITIONS - Full Definitions field. Independent claims are also included for: (1) Linkers of formula (IIIa) where RG = RG1 (III1), where RG = RG2 (III2), where RG = RG3 (III3), and formula (IVa) where RG = RG1 (IV1), where RG = RG2 (IV2), where RG = RG3 (IV3); and (2) Effector recognition unit conjugate of formula (I'). In formula (I1), FG1 = 1-10C alkyl S3 or Z1 and at least one FG2a or FG2b; FG2a = -S-S, S-substituted Z1; where Z1 = hydantoin, C(=O)CH=CH, C(=O)-C(Br)=C, C(=O)-C(Cl)=S, S(=O)2C=C; FG2b = CONH; RG1 = O=C=N or S=C=N; RG2 = Hal-C(=T)-CHR22, Hal-C(=T)-CHR22-NR23-C(=T), R26 = 1-10C alkyl, aryl or aralkyl; and RG3 = OH, NHR24a or COOH. Provided that in formula (III3), compound 1-(4-amino-phenyl)-pyrrole-2,5-dione is not included.

Description

Die Entwicklung des Verständnisses betreffend die Erkennung von Bindungsregionen, insbesondere auf dem Gebiet der monoklonalen Antikörper oder deren Fragmente gegen spezifische Tumor-Antigene, ermöglicht es, an eine selektive Tumor-Therapie durch gezielte Freisetzung eines Anti-Tumor-Wirkstoffes am Zielort zu denken.The development of understanding regarding the recognition of binding regions, in particular on the field of monoclonal antibodies or their fragments against specific tumor antigens it, selective tumor therapy through targeted release an anti-tumor agent to think at the destination.

Voraussetzung für einen derartigen Ansatz, bei dem ein hoch aktiver (toxischer) Wirkstoff (Effektor) an eine hochmolekulare Tumor-spezifische Erkennungseinheit wie beispielsweise an einen Antikörper gekuppelt wird, ist eine weitgehende Inaktivität des Konjugates, dessen Mindestbestandteile eine Erkennungseinheit und einen Effektor darstellen, bis dieses den Zielort (Tumor) erreicht hat. Am Zielort angelangt, bindet das Konjugat an der Zelloberfläche und der Wirkstoff kann, gegebenenfalls nach vorangegangener Internalisierung des gesamten Komplexes, freigesetzt werden.Prerequisite for such an approach where a highly active (toxic) active ingredient (effector) high molecular tumor-specific recognition unit such as to an antibody is coupled is a substantial inactivity of the conjugate, its minimum components represent a recognition unit and an effector until this has reached the destination (tumor). When you arrive at the destination, that binds Conjugate on the cell surface and the active ingredient can, if appropriate after previous internalization of the entire complex.

Die erfolgreiche Therapie solider Tumore, insbesondere mit monoklonalen Antikörpern, kann jedoch eingeschränkt werden durch eine unzureichende Penetration des Antikörpers in den Tumor sowie die heterogene Verteilung des entsprechenden tumorassoziierten Antigens im Tumorgewebe.Successful therapy more solid Tumors, especially those with monoclonal antibodies, can be restricted due to inadequate penetration of the antibody into the tumor as well as the heterogeneous distribution of the corresponding tumor-associated antigen in tumor tissue.

Diese Einschränkungen könnten dadurch umgangen werden, dass man in spezifischer Weise das Tumor-Gefäßsystem angreift. Das Wachstum von Tumoren unterhalb eines Volumens von etwa 2 mm3 ist abhängig von einer Neoangiogenese. Das weitere Tumorwachstum basiert auf einem intakten Gefäßsystem, das die Versorgung mit Nährstoffen bzw. Entsorgung von Abfallprodukten gewährleistet. Die selektive Zerstörung dieses Systems sollte deshalb zu einem Absterben des Tumors führen. Der Angriff auf das Gefäßsystem des Tumors verspricht gegenüber dem direkten Angriff auf den Tumor selbst eine Reihe von Vorteilen. Im Vergleich zu Tumorzellen sind Endothelzellen leichter zugänglich, da kein Tumorgewebe penetriert werden muß. Die Schädigung eines einzelnen Tumorgezfäßes sollte zum Absterben tausender Tumorzellen führen. Um ein Tumorgefäß zu schädigen, besteht keine Notwendigkeit, alle Endothelzellen abzutöten. Der spezifische Angriff von Endothelzellen in oder in der Nähe von Tumoren minimiert systemische Nebenwirkungen. Endothelzellen sind genetisch sehr stabil, so dass die Wahrscheinlichkeit einer Resistenzentwicklung gegen das Tumortherapeutikum gering ist.These limitations could be circumvented by specifically targeting the tumor vasculature. The growth of tumors below a volume of approximately 2 mm 3 depends on neoangiogenesis. Further tumor growth is based on an intact vascular system that ensures the supply of nutrients and the disposal of waste products. The selective destruction of this system should therefore lead to the death of the tumor. Attacking the tumor vascular system promises a number of advantages over directly attacking the tumor itself. Compared to tumor cells, endothelial cells are more accessible because no tumor tissue has to be penetrated. Damage to a single tumor container should lead to the death of thousands of tumor cells. In order to damage a tumor vessel, there is no need to kill all endothelial cells. The specific attack of endothelial cells in or near tumors minimizes systemic side effects. Endothelial cells are genetically very stable, so the likelihood of developing resistance to the tumor therapeutic is low.

Im Rahmen der vorliegenden Erfindung wurde nun überraschenderweise eine Möglichkeit gefunden, die chemisch sehr empfindliche, hochfunktionalisierte Wirkstoffklasse der Epothilone und ihrer Analoga mit einer hochmolekularen Erkennungseinheit über unterschiedliche Linker an unterschiedliche Positionen des Wirkstoffes zu knüpfen.Within the scope of the present invention was now surprisingly a possibility found the chemically very sensitive, highly functionalized Drug class of epothilones and their analogs with a high molecular weight Recognition unit via different linkers to different positions of the active ingredient to tie.

Der vorliegenden Erfindung liegt somit unter anderem die Aufgabe zugrunde,The present invention lies among other things, the task

  • 1. eine Methode zu finden, hoch aktive Wirkstoffe aus der Strukturklasse der Epothilone und Epothilon-Derivate mit geeigneten Linkern zu verknüpfen,1. Find a method of using highly active ingredients from the structural class of epothilones and epothilone derivatives link suitable linkers,
  • 2. geeignete Linker zu synthetisieren,2. to synthesize suitable linkers,
  • 3. eine Methode zu entwickeln, diese Epothilon-Linker Konjugate mit Erkennungseinheiten wie beispielsweise monoklonalen Antikörpern oder deren Fragmenten zu Immunkonjugaten zu verknüpfen, die sowohl chemisch als auch metabolisch für eine Arzneimittelentwicklung ausreichend stabil sind und die hinsichtlich ihrer therapeutischen Breite, ihrer Selektivität der Wirkung und/oder unerwünschter toxischer Nebenwirkungen und/oder ihrer Wirkstärke den zu Grunde liegenden Epothilonen bzw. Epothilon-Derivaten überlegen sind.3. Develop a method to conjugate these epothilone linkers with recognition units such as monoclonal antibodies or to link their fragments to immunoconjugates, both chemically and also metabolically for a drug development are sufficiently stable and the in terms of their therapeutic breadth, their selectivity of action and / or undesirable toxic side effects and / or their potency the underlying Epothilones or epothilone derivatives are superior.

Die vorliegende Erfindung umfasst entsprechend Effektorkonjugate der allgemeinen Formel 1

Figure 00030001
worin
R1a, R1b unabhängig voneinander Wasserstoff, C1-C10 Alkyl, Aryl, Aralkyl, oder gemeinsam eine -(CH2)m-Gruppe sind, worin m 2 bis 5 ist,
R2a, R2b unabhängig voneinander Wasserstoff, C1-C10 Alkyl, Aryl, Aralkyl, oder gemeinsam eine -(CH2)n-Gruppe sind, worin n 2 bis 5 ist, oder C2-C10 Alkenyl, oder C2-C10 Alkinyl,
R3 Wasserstoff, C1-C10 Alkyl, Aryl oder Aralkyl, und
R4a, R4b unabhängig voneinander Wasserstoff, C1-C10 Alkyl, Aryl, Aralkyl, oder gemeinsam eine -(CH2)p-Gruppe sind, worin p 2 bis 5 ist,
R5 Wasserstoff, C1-C10 Alkyl, Aryl, Aralkyl, CO2H, CO2Alkyl, CH2OH, CH2OAlkyl, CH2OAcyl, CN, CH2NH2, CH2N(Alkyl, Acyl)1,2, oder CH2Hal,
Hal ein Halogen-Atom,
R6, R7 jeweils Wasserstoff, oder gemeinsam eine zusätzliche Bindung, oder gemeinsam ein Sauerstoff-Atom, oder gemeinsam eine NH-Gruppe, oder gemeinsam eine N-Alkyl-Gruppe, oder gemeinsam eine CH2-Gruppe, und
G ein Sauerstoffatom oder CH2 sind,
D–E eine Gruppe H2C-CH2, HC=CH, C≡C, CH(OH)-CH(OH), CH(OH)-CH2,
CH2-CH(OH), HC O / -CH, O-CH2, oder, falls G eine CH2-Gruppe darstellt, CH2-O ist,
W eine Gruppe C(=X)R8, oder ein bi- or tricyclischer aromatischer oder heteroaromatischer Rest ist,
L3 Wasserstoff ist, oder, falls ein Rest in W eine Hydroxyl-Gruppe enthält, mit dieser eine Gruppe O-L4 bildet, oder, falls ein Rest in W eine Amino-Gruppe enthält, mit dieser eine Gruppe NR25-L4 bildet,
R25 Wasserstoff oder C1-C10 Alkyl ist,
X ein Sauerstoffatom, oder zwei OR20-Gruppen, oder eine C2-C10 Alkylendioxy Gruppe, die geradkettig oder verzweigt sein darf, oder H/OR9, oder eine CR10R11-Gruppe,
R8 Wasserstoff, C1-C10 Alkyl, Aryl, Aralkyl, Halogen oder CN, und
R9 Wasserstoff oder eine Schutzgruppe PGX sind,
R10, R11 jeweils unabhängig voneinander Wasserstoff, C1-C20 Alkyl, Aryl, Aralkyl sind, oder gemeinsam mit einem Methylenkohlenstoffatom einen 5- bis 7-gliedrigen carbocyclischen Ring bilden,
Z Sauerstoff oder H/OR12,
R12 Wasserstoff oder eine Schutzgruppe PGZ,
A-Y eine Gruppe O-C(=O), O-CH2, CH2-C(=O), NR21-C(=O) oder NR21-SO2,
R20 C1-C20 Alkyl,
R21 ein Wasserstoffatom oder C1-C10 Alkyl,
PGX, PGY, PGZ eine Schutzgruppe PG, und
L1, L2, L4 unabhängig voneinander Wasserstoff, eine Gruppe C(=O)Cl, eine Gruppe C(=S)CI, eine Gruppe PGY oder einen Linker der allgemeinen Formel III darstellen können;
mit der Bedingung, dass mindestens ein Substituent L1, L2 oder L4 einen Linker der allgemeinen Formel (III) darstellt;
der Linker der allgemeinen Formel (III) folgende Struktur hat,
Figure 00050001
worin
T Sauerstoff oder Schwefel,
U Sauerstoff, CHR22, CHR22-NR23-C(=O)-, CHR22-NR23-C(=S)-, O-C(=O)-CHR22-NR23-C(=O)-, O-C(=O)-CHR22-NR23-C(=S)- oder NR24a,
o 0 bis 15,
V eine Bindung, Aryl, eine Gruppe
Figure 00050002
oder eine Gruppe
Figure 00050003
s 0 bis 4,
Q eine Bindung, O-C(=O)-NR24c, O-C(=S)-NR24c,
Figure 00060001
R22 Wasserstoff, C1-C10 Alkyl, Aryl oder Aralkyl
R23 Wasserstoff oder C1-C10 Alkyl,
R24a, R24b, R24c unabhängig voneinander Wasserstoff oder C1-C10 Alkyl,
q 0 bis 15,
Figure 00060002
darstellen können;
als einheitliches Isomer oder eine Mischung unterschiedlicher Isomere und/oder als ein pharmazeutisch akzeptables Salz hiervon.The present invention accordingly comprises effector conjugates of the general formula 1
Figure 00030001
wherein
R 1a , R 1b independently of one another hydrogen, C 1 -C 10 alkyl, aryl, aralkyl, or together a - (CH 2 ) m group are pe, where m is 2 to 5,
R 2a , R 2b independently of one another are hydrogen, C 1 -C 10 alkyl, aryl, aralkyl, or together are a - (CH 2 ) n group, in which n is 2 to 5, or C 2 -C 10 alkenyl, or C 2 -C 10 alkynyl,
R 3 is hydrogen, C 1 -C 10 alkyl, aryl or aralkyl, and
R 4a , R 4b independently of one another are hydrogen, C 1 -C 10 alkyl, aryl, aralkyl, or together are a - (CH 2 ) p group, in which p is 2 to 5,
R5 is hydrogen, C 1 -C 10 alkyl, aryl, aralkyl, CO 2 H, CO 2 alkyl, CH 2 OH, CH 2 O alkyl, CH 2 O acyl, CN, CH 2 NH 2 , CH 2 N (alkyl, acyl) 1 , 2 , or CH 2 Hal,
Hal is a halogen atom,
R 6 , R 7 are each 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 CH 2 group, and
G is an oxygen atom or CH 2 ,
DE a group H 2 C-CH 2 , HC = CH, C≡C, CH (OH) -CH (OH), CH (OH) -CH 2 ,
CH2-CH (OH), HC O / -CH, O-CH 2 , or, if G represents a CH 2 group, CH 2 -O,
W is a group C (= X) R 8 , 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-L4 with it, or, if a radical in W contains an amino group, forms a group NR 25 -L 4 with it .
R 25 is hydrogen or C 1 -C 10 alkyl,
X represents an oxygen atom, or two OR 20 groups, or a C 2 -C 10 alkylenedioxy group, which may be straight-chain or branched, or H / OR 9 , or a CR 10 R 11 group,
R 8 is hydrogen, C 1 -C 10 alkyl, aryl, aralkyl, halogen or CN, and
R 9 are hydrogen or a protective group PG X ,
R 10 , R 11 are each independently hydrogen, C 1 -C 20 alkyl, aryl, aralkyl, or together with a methylene carbon atom form a 5- to 7-membered carbocyclic ring,
Z oxygen or H / OR 12 ,
R 12 is hydrogen or a protective group PG Z ,
AY is a group OC (= O), O-CH 2 , CH 2 -C (= O), NR 21 -C (= O) or NR 21 -SO 2 ,
R 20 C 1 -C 20 alkyl,
R 21 is a hydrogen atom or C 1 -C 10 alkyl,
PG X , PG Y , PG Z a protective group PG, and
L 1 , L 2 , L 4 can independently represent hydrogen, a group C (= O) Cl, a group C (= S) CI, a group PGY or a linker of the general formula III;
with the condition that at least one substituent L 1 , L 2 or L 4 represents a linker of the general formula (III);
the linker of the general formula (III) has the following structure,
Figure 00050001
wherein
T oxygen or sulfur,
U oxygen, CHR 22 , CHR 22 -NR 23 -C (= O) -, CHR 22 -NR 23 -C (= S) -, OC (= O) -CHR 22 -NR 23 -C (= O) - , OC (= O) -CHR 22 -NR 23 -C (= S) - or NR 24a ,
o 0 to 15,
V a bond, aryl, a group
Figure 00050002
or a group
Figure 00050003
s 0 to 4,
Q is a bond, OC (= O) -NR 24c , OC (= S) -NR 24c ,
Figure 00060001
R 22 is hydrogen, C 1 -C 10 alkyl, aryl or aralkyl
R 23 is hydrogen or C 1 -C 10 alkyl,
R 24a , R 24b , R 24c independently of one another are hydrogen or C 1 -C 10 alkyl,
q 0 to 15,
Figure 00060002
can represent;
as a uniform isomer or a mixture of different isomers and / or as a pharmaceutically acceptable salt thereof.

Die Erfindung beschreibt weiterhin die Herstellung von Effektor-Erkennungseinheit-Konjugaten der allgemeinen Formel (1), wobei die Substituenten darin die obengenannten Bedeutungen haben, jedoch mindestens eine Gruppe FG1 durch eine Gruppe FG2 ersetzt ist, wobei FG2 die folgenden Bedeutungen haben kann:

Figure 00060003
und wobei eine Erkennungseinheit über ein Schwefelatom mit der Gruppe FG2 konjugiert ist;
wobei die Erkennungseinheit beispielsweise ein Peptid, ein löslicher Rezeptor, ein Cytokin, ein Lymphokin, ein Aptamer, ein Spiegelmer, ein rekombinantes Protein, eine Framework-Struktur, ein monoklonaler Antikörper oder ein Fragment eines monoklonalen Antikörpers sein kann.The invention further describes the production of effector-recognition unit conjugates of the general formula (1), the substituents therein having the meanings given above, but at least one group FG 1 having been replaced by a group FG 2 , where FG 2 can have the following meanings :
Figure 00060003
and wherein a recognition unit is conjugated to the group FG2 via a sulfur atom;
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.

Gemäss dieser Erfindung können die genannten Effektor-Erkennungseinheit-Konjugate eine oder mehrere Erkennungseinheiten umfassen; dabei können die einem Konjugat zugehörigen Erkennungseinheiten identisch oder verschieden sein. Es ist bevorzugt, dass die Erkennungseinheiten eines Konjugats identisch sind.According to this invention, the called effector recognition unit conjugates one or more recognition units include; can those associated with a conjugate Detection units can be identical or different. It is preferred that the recognition units of a conjugate are identical.

Die erfindungsgemäßen Konjugate werden vorzugsweise für die Behandlung von Erkrankungen, die mit proliferativen Prozessen verknüpft sind, eingesetzt. Beispielsweise genannt seien die Therapie unterschiedlichster Tumore, die Therapie entzündlicher und/oder neurodegenerativer Erkrankungen wie der Multiplen Sklerose oder der Alzheimerschen Erkrankung, die Therapie Angiogenese-assoziierter Erkankungen wie das Wachstum solider Tumore, die rheumatoide Arthritis oder Erkrankungen des Augenhintergrundes.The conjugates of the invention are preferred for the Treatment of diseases associated with proliferative processes, used. For example, the most varied of therapies are mentioned Tumors, inflammatory therapy and / or neurodegenerative diseases such as multiple sclerosis or Alzheimer's disease, therapy associated with angiogenesis Diseases such as the growth of solid tumors, rheumatoid arthritis or diseases of the fundus.

Die Darstellung der Epothilone, ihrer Vorstufen und Derivate der allgemeinen Formel I erfolgt nach den dem Fachmann bekannten Methoden wie sie beispielsweise in DE 19907588 , WO 98/25929, WO 99/58534, WO 99u/2514, WO 99/67252, WO 99/67u253, WO 99/7692, EP 99/4915, WO 00/485, WO 00/1333, WO 00/u66589, 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/u58286, US 02/62030, WO 02/32844, WO 02/30356, WO 02/32844, WO 02/14323, WO 02/8440 beschrieben sind.The epothilones, their precursors and derivatives of the general formula I are prepared by the methods known to the person skilled in the art, for example in DE 19907588 , WO 98/25929, WO 99/58534, WO 99u / 2514, WO 99/67252, WO 99 / 67u253, WO 99/7692, EP 99/4915, WO 00/485, WO 00/1333, WO 00 / u66589 , 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 / u58286, US 02/62030, WO 02/32844, WO 02/30356, WO 02/32844, WO 02/14323, WO 02/8440 are described.

Als Alkylgruppen R1 a, R1b, R2a, R2b, R3, R4a, R4b, R5, R8, R10, R11, R20, R21, R22, R23, R24a, R24b, R24c, R25 und R26 sind gerad- oder verzweigtkettige Alkylgruppen mit 1–20 Kohlenstoffatomen zu betrachten, wie beispielsweise Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.-Butyl, Pentyl, Isopentyl, Neopentyl, Heptyl, Hexyl, Decyl.As alkyl groups R 1 a , R 1b , R 2a , R 2b , R 3 , R 4a , R 4b , R 5 , R 8 , R 10 , R 11 , R 20 , R 21 , R 22 , R 23 , R 24a , R 24b , R 24c , R 25 and R 26 are straight or branched chain alkyl groups with 1-20 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl , Heptyl, hexyl, decyl.

Die Alkylgruppen R1a, R1b, R2a, R2b, R3, R4a, R4b, R5, R8, R10, R11, R20, R21, R22, R23, R24a, R24b, R24c, R25 und R26 können ferner perfluoriert oder substituiert sein durch 1-5 Halogenatome, Hydroxygruppen, C1-C4-Alkoxygruppen oder C6-C12-Arylgruppen (die durch 1-3 Halogenatome substituiert sein können).The alkyl groups R 1a , R 1b , R 2a , R 2b , R 3 , R 4a , R 4b , R 5 , R 8 , R 10 , R 11 , R 20 , R 21 , R 22 , R 23 , R 24a , R 24b , R 24c , R 25 and R 26 can also be perfluorinated or substituted by 1-5 halogen atoms, hydroxy groups, C1-C4 alkoxy groups or C 6 -C 12 aryl groups (which can be substituted by 1-3 halogen atoms).

Als Arylrest R1a, R1b, R2a, R2b, R3, R4a, R4b, R5, R8, R10, R11, R22, R26 und V kommen substituierte und unsubstituierte carbocyclische oder heterocyclische Reste mit einem oder mehreren Heteroatomen wie Phenyl, Naphthyl, Furyl, Thienyl, Pyridyl, Pyrazolyl, Pyriumidinyl, Oxazolyl, Pyridazinyl, Pyrazinyl, Chinolyl, Thiazolyl, Benzothiazolyl oder Benzoxazolyl, die einfach oder mehrfach substituiert sein können durch Halogen, OH, O-Alkyl, CO2H, CO2-Alkyl, -NH2, -NO2, -N3, -CN, C1-C20-Alkyl, C1-C20-Acyl oder C1-C20-Acyloxy-Gruppen, in Frage. Die Heteroatome können oxidiert sein, sofern dadurch der aromatischen Charakter nicht verloren geht, wie beispielsweise die Oxidation eines Pyridyls zu einem Pyridyl-N-Oxid.Aryl radicals R 1a , R 1b , R 2a , R 2b , R 3 , R 4a , R 4b , R 5 , R 8 , R 10 , R 11 , R 22 , R 26 and V are substituted and unsubstituted carbocyclic or heterocyclic radicals with one or more heteroatoms such as phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyriumidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl, benzothiazolyl or benzoxazolyl, which can be mono- or polysubstituted by halogen, OH, O-alkyl, CO 2 H, CO 2 alkyl, -NH 2 , -NO 2 , -N 3 , -CN, C 1 -C 20 alkyl, C 1 -C 20 acyl or C 1 -C 20 acyloxy groups, in question. The heteroatoms can be oxidized if the aromatic character is not lost as a result goes, such as the oxidation of a pyridyl to a pyridyl-N-oxide.

Als bi- und tricyclische Arylreste W kommen substituierte und unsubstituierte carbocyclische oder heterocyclische Reste mit einem oder mehreren Heteroatomen wie Naphthyl, Anthryl, Benzothiazolyl, Benzoxazolyl, Benzimidazolyl, Chinolyl, Isochinolyl, Benzoxaziyl, Benzofuranyl, Indolyl, Indazolyl, Chinoxalinyl, Tetrahydroisochinolinyl, Tetrahydrochinolinyl, Thienopyridinyl, Pyridopyridinyl, Benzopyrazolyl, Benzotriazolyl, oder Dihydroindolyl, die einfach oder mehrfach substituiert sein können durch Halogen, OH, O-Alkyl, CO2H, CO2-Alkyl, -NH2, -NO2, -N3, -CN, C1-C20-Alkyl, C1-C20-Acyl oder C1-C20-Acyloxy-Gruppen, in Frage. Die Heteroatome können oxidiert sein, sofern dadurch der aromatische Charakter nicht verloren geht, wie beispielsweise die Oxidation eines Chinolyls zu einem Chinolyl-N-Oxid.The bi- and tricyclic aryl radicals W are substituted and unsubstituted carbocyclic or heterocyclic radicals having one or more heteroatoms, such as naphthyl, anthryl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolyl, isoquinolyl, benzoxaziyl, benzofuranyl, tolokinololoxyloloxyloloxyloloxyloloxyloloxyloloxyloloxyloloxyloloxyloloxyloloxyloloxyloloxyloloxinolyloxynololoxinololoxinololoxinololoxinololoxololoxinololoxololoxinololoxinololoxinololoxinololoxinololoxyloloxinololoxylolinoxyloloxin, , Pyridopyridinyl, benzopyrazolyl, benzotriazolyl, or dihydroindolyl, which can be mono- or polysubstituted by halogen, OH, O-alkyl, CO 2 H, CO 2 -alkyl, -NH 2 , -NO 2 , -N 3 , -CN, C 1 -C 20 alkyl, C 1 -C 20 acyl or C 1 -C 20 acyloxy groups, in question. The heteroatoms can be oxidized, provided that the aromatic character is not lost, such as the oxidation of a quinolyl to a quinolyl-N-oxide.

Die Aralkylgruppen in R1a, R1b, R2a, R2b, R3, R4a, R4b, R5, R8, R10, R11, R22 und R26 können im Ring bis 14 C-Atome, bevorzugt 6 bis 10 und in der Alkylkette 1 bis 8, bevorzugt 1 bis 4 Atome enthalten. Als Aralkylreste kommen beispielweise in Betracht Benzyl, Phenylethyl, Naphthylmethyl, Naphthylethyl, Funlmethyl, Thienylethyl oder Pyridylpropyl. Die Ringe können einfach oder mehrfach substituiert sein durch Halogen, OH, O-Alkyl, CO2H, CO2-Alkyl, -NO2, -N3, -CN, C1-C20-Alkyl, C1-C20-Acyl oder C1-C20-Acyloxy-Gruppen.The aralkyl groups in R 1a , R 1b , R 2a , R 2b , R 3 , R 4a , R 4b , R 5 , R 8 , R 10 , R 11 , R 22 and R 26 can contain up to 14 carbon atoms in the ring, preferably contain 6 to 10 and in the alkyl chain 1 to 8, preferably 1 to 4 atoms. Examples of suitable aralkyl radicals are benzyl, phenylethyl, naphthylmethyl, naphthylethyl, funlmethyl, thienylethyl or pyridylpropyl. The rings can be mono- or polysubstituted by halogen, OH, O-alkyl, CO 2 H, CO 2 alkyl, -NO 2 , -N 3 , -CN, C 1 -C 20 alkyl, C 1 -C 20 -Acyl or C 1 -C 20 -acyloxy groups.

Als Vertreter für die Schutzgruppen PG sind tris(C1-C20 Alkyl)silyl, bis(C1-C20 Alkyl)-Arylsilyl, (C1-C20 Alkyl)-Dianlsilyl, tris(Aralkyl)-Silyl, C1-C20-Alkyl, C4-C7-Cycloalkyl, das im Ring zusätzlich ein Sauerstoffatom enthalten kann, Alkyl, C7-C20-Aralkyl, C1-C20-Acyl, Aroyl, C1-C20-Alkylsulfonyl sowie Arylsulfonyl zu nennen.Representing the protective groups PG are tris (C 1 -C 20 alkyl) silyl, bis (C 1 -C 20 alkyl) arylsilyl, (C 1 -C 20 alkyl) dianlsilyl, tris (aralkyl) silyl, C 1 -C 20 alkyl, C 4 -C 7 cycloalkyl, which may additionally contain an oxygen atom in the ring, alkyl, C 7 -C 20 aralkyl, C 1 -C 20 acyl, aroyl, C 1 -C 20 alkylsulfonyl as well as arylsulfonyl.

Als Alkyl-, Silyl- und Acylreste für die Schutzgruppen PG kommen insbesondere die dem Fachmann bekannten Reste in Betracht. Bevorzugt sind aus den entsprechenden Alkyl- und Silylethern leicht abspaltbare Alkyl- bzw. Silylreste, wie beispielsweise der Methoxymethyl-, Methoxyethyl, Ethoxyethyl-, Tetrahydropyranyl-, Tetrahydrofuranyl-, Trimethylsilyl-, Triethylsilyl-, tert.-Butyldimethylsilyl-, tert.-Butyldiphenylsilyl-, Tribenzylsilyl-, Triisopropylsilyl-, Benzyl, para-Nitrobenzyl-, para-Methoxybenzyl-Rest sowie Alkylsulfonyl- und Arylsulfonylreste. Als Acylreste kommen z.B. Formyl, Acetyl, Propionyl, Isopropionyl, Trichlormethylcarbonyl, Pivalyl-, Butyryl oder Benzoyl, die mit Amino- und/oder Hydroxygruppen substituiert sein können, in Frage.As alkyl, silyl and acyl residues for the Protecting groups PG come in particular those known to the person skilled in the art Leftovers into consideration. Preferred from the corresponding alkyl and silyl ethers easily removable alkyl or silyl radicals, such as the methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, Trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, Tribenzylsilyl, triisopropylsilyl, benzyl, para-nitrobenzyl, para-methoxybenzyl radical and alkylsulfonyl and arylsulfonyl radicals. As acyl residues are e.g. Formyl, acetyl, propionyl, isopropionyl, Trichloromethylcarbonyl, pivalyl, butyryl or benzoyl, with Amino and / or hydroxy groups can be substituted in Question.

Als Aminoschutzgruppen PG kommen die dem Fachmann bekannten Reste in Betracht. Beispielsweise genannt seien die Alloc-, Boc-, Z-, Benzyl, f-Moc-, Troc-, Stabase- oder Benzostabase-Gruppe.PG come as amino protecting groups the radicals known to the person skilled in the art. For example called be the Alloc, Boc, Z, Benzyl, f-Moc, Troc, Stabase or Benzostabase group.

Als Halogen-Atome kommen in Betracht Fluor, Chlor, Brom oder Iod.Halogen atoms are suitable Fluorine, chlorine, bromine or iodine.

Die Acylgruppen können 1 bis 20 Kohlenstoffatome enthalten, wobei Formyl-, Acetyl-, Propionyl-, Isopropionyl und Pivalylgruppen bevorzugt sind.The acyl groups can have 1 to 20 carbon atoms contain, wherein formyl, acetyl, propionyl, isopropionyl and Pivalyl groups are preferred.

Die für X mögliche C2-C10-Alkylen-α,ω-dioxygruppe ist vorzugsweise eine Ethylenketal- oder Neopentylketalgruppe.The C 2 -C 10 -alkylene-α, ω-dioxy group which is possible for X is preferably an ethylene ketal or neopentyl ketal group.

Bevorzugte Verbindungen der allgemeinen Formel 1 sind solche, bei denen A-Y O-C(=O) oder NR21-C(=O), D-E eine H2C-CH2-Gruppe, G eine CH2-Gruppe, Z ein Sauerstoffatom, R1a, R1b jeweils C1-C10 Alkyl oder zusammen eine -(CH2)p-Gruppe mit p gleich 2 oder 3 oder 4, R2a, R2b unabhängig voneinander Wasserstoff, C1-C10 Alkyl, C2-C10 Alkenyl, oder C2-C10 Alkinyl, R3 Wasserstoff; R4a, R4b unabhängig voneinander Wasserstoff oder C1-C10 Alkyl; R5 Wasserstoff, oder C1-C4 Alkyl oder CH2OH oder CH2NH2 oder CH2N(Alkyl, Acyl)1,2 oder CH2Hal, R6 und R7 gemeinsam eine zusätzliche Bindung oder gemeinsam eine NH-Gruppe oder gemeinsam eine N-Alkyl-Gruppe oder gemeinsam eine CH2-Gruppe oder gemeinsam ein Sauerstoffatom, W eine Gruppe C(=X)R8 oder ein 2-Methylbenzothiazol-5-yl-Radikal oder ein 2-Methylbenzoxazol-5-yl-Radikal oder ein Chinolin-7-yl-Radikal oder ein 2-Aminomethylbenzothiazol-5-yl-Radikal oder ein 2-Hydroxymethylbenzothiazol-5-yl-Radikal oder ein 2-Aminomethylbenzoxazol-5-yl-Radikal oder ein 2-Hydroxymethylbenzoxazol-5-yl-Radikal, X eine CR10R11-Gruppe, R8 Wasserstoff oder C1-C4 Alkyl oder ein Fluoratom oder ein Chloratom oder ein Bromatom, R10/R11 Wasserstoff/2-Methylthiazol-4-yl oder Wasserstoff/2-Pyridyl oder Wasserstoff/2-Methyloxazol-4-yl oder Wasserstoff/2-Aminomethylthiazol-4-yl oder Wasserstoff/2-Aminomethyloxazol-4-yl oder Wasserstoff/2-Hydroxymethylthiazol-4-yl oder Wasserstoff/2-Hydroxymethyloxazol-4-yl darstellen.Preferred compounds of the general formula 1 are those in which AY OC (= O) or NR 21 -C (= O), DE an H 2 C-CH 2 group, G a CH 2 group, Z an oxygen atom, R 1a , R 1b each C 1 -C 10 alkyl or together a - (CH 2 ) p group with p equal to 2 or 3 or 4, R 2a , R 2b independently of one another hydrogen, C 1 -C 10 alkyl, C 2 - C 10 alkenyl, or C 2 -C 10 alkynyl, R 3 hydrogen; R 4a , R 4b independently of one another are hydrogen or C 1 -C 10 alkyl; R5 is hydrogen, or C 1 -C 4 alkyl or CH 2 OH or CH2NH 2 or CH 2 N (alkyl, acyl) 1,2 or CH 2 Hal, R 6 and R 7 together 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 a group C (= X) R 8 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 is a CR 10 R 11 group, R8 is hydrogen or C 1 -C 4 alkyl or a fluorine atom or a chlorine atom or a bromine atom, R 10 / R 11 is 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-hydroxym represent ethyloxazol-4-yl.

Als Linker der allgemeinen Formel (III) sind Verbindungen bevorzugt, bei denen V eine Bindung oder einen Arylrest und T Sauerstoff darstellen und o gleich Null ist.As a linker of the general formula (III) Compounds are preferred in which V is a bond or a Aryl radical and T represent oxygen and o is zero.

Als rekombinante Proteine zur Verwendung als Erkennungseinheit kommen beispielsweise aus von Antikörpern abgeleitete Bindungsregionen, sogenannte CDRs in Frage.For use as recombinant proteins the recognition unit comes, for example, from antibodies derived from antibodies Binding regions, so-called CDRs in question.

Als Framework-Strukturen zur Verwendung als Erkennungseinheit kommen beispielsweise hochmolekulare Strukturen, die nicht von Antikörpern abgeleitet sind, in Frage. Beispielsweise genannt seien Strukturen vom Fibronektin-Typ 3 und von Crystallinen.Use as framework structures high-molecular structures come as a recognition unit, that are not from antibodies are in question. For example, structures are mentioned fibronectin type 3 and crystalline.

Als Fragmente monoklonaler Antikörper zur Verwendung als Erkennungseinheit seien beispielsweise genannt single-chain Fuv, Fab, F(ab) sowie rekombinante Multimere.As fragments of monoclonal antibodies Use as a recognition unit may be mentioned, for example, as a single chain Fuv, Fab, F (from)  as well as recombinant multimers.

Als bevorzugte Erkennungseinheiten kommen solche in Betracht, die sich beispielweise für die Erkennung und/oder Diagnose und/oder Therapie von soliden Tumoren und malignen Erkrankungen des hämatopoetischen Systems eignen.As preferred recognition units come into consideration, for example, for the detection and / or diagnosis and / or therapy of solid tumors and malignancies Haematopoietic diseases Systems are suitable.

Als weiterhin bevorzugte Erkennungseinheiten kommen solche in Betracht, die eine selektive Erkennung des erkrankungsspezifischen Gefäßsystems, vorzugsweise der Angiogenese, ermöglichen.As further preferred recognition units come into consideration those who selectively recognize the disease-specific Vascular system, preferably angiogenesis.

Tabelle 1 führt Beispiele für besonders bevorzugte Erkennungseinheiten zur Behandlung solider Tumoren auf. TABELLE 1

Figure 00110001
Figure 00120001
Figure 00130001
Figure 00140001
Figure 00150001
Figure 00160001
Figure 00170001
Figure 00180001
Figure 00190001
Table 1 lists examples of particularly preferred recognition units for the treatment of solid tumors. TABLE 1
Figure 00110001
Figure 00120001
Figure 00130001
Figure 00140001
Figure 00150001
Figure 00160001
Figure 00170001
Figure 00180001
Figure 00190001

Als besonders bevorzugte Erkennungseinheiten zur Behandlung hämatologischer Tumore seien ferner Antikörper oder Antikörperfragmente wie CD19, CD20, CD40, CD22, CD25, CD5, CD52, CD10, CD2, CD7, CD33, CD38, CD40, CD72, CD4, CD21, CD5, CD37 und CD30 genannt.As a particularly preferred recognition unit for the treatment of haematological Tumors are also antibodies or antibody fragments like CD19, CD20, CD40, CD22, CD25, CD5, CD52, CD10, CD2, CD7, CD33, CD38, CD40, CD72, CD4, CD21, CD5, CD37 and CD30 called.

Als besonders bevorzugte Erkennungseinheiten zur anti-angiogenen Therapie seien ferner Antikörper oder deren Fragmente wie VCAM, CD31, ELAM, Endoglin, VEGFRI/II, αvβ3, Tie1/2, TES23 (CD44ex6), Phosphatidylserin, PSMA, VEGFR/VEGF-Komplex oder ED-B-Fibronectin genannt.Antibodies or their fragments such as VCAM, CD31, ELAM, Endoglin, VEGFRI / II, α v β 3 , Tie1 / 2, TES23 (CD44ex6), phosphatidylserine, PSMA, VEGFR / VEGF- are also particularly preferred recognition units for anti-angiogenic therapy. Called complex or ED-B fibronectin.

Die nachstehend genannten Verbindungen sind als Effektor-Grundkörper erfindungsgemäß besonders bevorzugt:
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion,
(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-dion,
(4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-Aminomethyl-thiazol-4-yl)-1-methyl-vinyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dion,
(1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(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-dion,
(1S,3S(E),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-1-methylvinyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion,
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4-yl)-1-methyl-vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion,
(4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-Aminomethyl-thiazol-4-yl)-1-methyl-vinyl]-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion,
(1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3-[1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S(E),7S,10R,11S,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[14.1.0]heptadecane-5,9-dion,
(1S,3S(E),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-1-methylvinyl]-7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-fluor-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-(2-(2-hydroxymethyl-thiazol-4-yl)-1-fluor-vinyl]-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dion,
(4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-thiazol-4-yl)-1-fluor-vinyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dion,
(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-fluor-2-(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-thiazol-4-yl)-1-fluor-vinyl]-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-1-fluor-vinyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-chlor-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4-yl)-1-chlor-vinyl]-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dion,
(4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-thiazol-4-yl)-1-chlor-vinyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dion,
(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-chlor-2-(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-thiazol-4-yl)-1-chlor-vinyl]-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-1-chlor-vinyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[1-fluor-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4-yl)-1-fluor-vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion,
(4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-thiazol-4-yl)-1-fluor-vinyl]-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion,
(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3-[1-fluor-2-(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-thiazol-4-yl)-1-fluor-vinyl]-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S(Z),7S,10R,11 S,12S,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-1-fluor-vinyl]-7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[1-chlor-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4-yl)-1-chlor-vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion,
(4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-thiazol-4-yl)-1-chlor-vinyl]-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion,
(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3-[1-chlor-2-(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-thiazol-4-yl)-1-chlor-vinyl]-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-1-chlor-vinyl]-7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-pyridyl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion,
(1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[1-methyl-2-(2-pyridyl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion,
(1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3-[1-methyl-2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-fluor-2-(2-pyridyl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion,
(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-fluor-2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-chlor-2-(2-pyridyl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion,
(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-chlor-2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[1-fluor-2-(2-pyridyl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion,
(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3-[1-fluor-2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[1-chlor-2-(2-pyridyl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion,
(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3-[1-chlor-2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion,
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4-yl)-1-methyl-vinyl]-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dion,
(4S,7R,8S,9S,13Z,16S(E))-16-(2-(2-Aminomethyl-oxazol-4-yl)-1-methyl-vinyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dion,
(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-dion,
(1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-oxazol-4-yl)-1-methyl-vinyl]-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S(E),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-1-methylvinyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[1-methyl-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion,
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-(2-(2-hydroxymethyl-oxazol-4-yl)-1-methyl-vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion,
(4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-Aminomethyl-oxazol-4-yl)-1-methyl-vinyl]-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion,
(1S,3S(E),7S,10R,11S,12S,16R)-7,11-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-dion,
(1S,3S(E),7S,10R,11S,12S,16R)-7,11-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]heptadecane-5,9-dion,
(1S,3S(E),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-1-methylvinyl]-7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-fluor-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4-yl)-1-fluor-vinyl]-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dion,
(4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-oxazol-4-yl)-1-fluor-vinyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dion,
(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-fluor-2-(2-methyl-oxazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-oxazol-4-yl)-1-fluor-vinyl]-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-1-fluor-vinyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-chlor-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4-yl)-1-chlor-vinyl]-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dion,
(4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-oxazol-4-yl)-1-chlor-vinyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dion,
(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-chlor-2-(2-methyl-oxazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-oxazol-4-yl)-1-chlor-vinyl]-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-1-chlor-vinyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[1-fluor-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4-yl)-1-fluor-vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-l3-ene-2,6-dion,
(4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-oxazol-4-yl)-1-fluor-vinyl]-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion,
(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3-[1-fluor-2-(2-methyl-oxazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-oxazol-4-yl)-1-fluor-vinyl]-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-1-fluor-vinyl]-7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[1-chlor-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dion,
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4-yl)-1-chlor-vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion,
(4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-oxazol-4-yl)-1-chlor-vinyl]-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dion,
(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3-[1-chlor-2-(2-methyl-oxazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-oxazol-4-yl)-1-chlor-vinyl]-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-1-chlor-vinyl]-7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(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-dion,
(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-dion,
(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-dion,
(1S,3S(E),7S,10R,11S,12S,16R)-7,11-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-dion,
(1S,3S(E),7S,10R,11S,12S,16R)-7,11-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-dion,
(1S,3S(E),7S,10R,11S,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-dion,
(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-dion,
(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-dion,
(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-dion,
(1S,3S(E),7S,10R,11S,12S,16R)-7,11-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-dion,
(1S,3S(E),7S,10R,11S,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-dion,
(1S,3S(E),7S,10R,11S,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-dion,
(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-dion,
(1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(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-dion,
(1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3-(2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-(2-methylbenzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dion,
(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-dion,
(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-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-(2-methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-benzothiazol-5-yl)-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-(2-methylbenzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dion,
(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-dion,
(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-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-benzothiazol-5-yl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S,7S,10R,11S,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-dion,
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-propyl-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dion,
(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-dion,
(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-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-propyl-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-benzothiazol-5-yl)-10-propyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S,7S,10R,11S,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-dion,
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-butyl-5,5,9,13-tetramethyl-16-(2-methylbenzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dion,
(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-dion,
(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-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-l0-butyl-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-benzothiazol-5-yl)-10-butyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,11-dihydroxy-10-butyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-allyl-5,5,9,13-tetramethyl-16-(2-methylbenzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dion,
(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-dion,
(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-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-allyl-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-benzothiazol-5-yl)-10-allyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,11-dihydroxy-10-allyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(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-dion,
(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-dion,
(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-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-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-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-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-dion,
(1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,11-dihydroxy-10-prop-2-inyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(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-l3-ene-2,6-dion,
(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-dion,
(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-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-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-dion,
(1S,3S,7S,10R,11S,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-dion,
(1S,3S,7S,10R,11S,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-dion,
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-but-3-inyl-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazolu-5-yl)-oxacyclohexadec-13-ene-2,6-dion,
(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-dion,
(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-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-but-3-inyl-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-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-dion,
(1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,11-dihydroxy-10-but-3-inyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-(2-methylbenzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dion,
(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-dion,
(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-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-(2-methyl-benzoxazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-benzoxazol-5-yl)-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-(2-methylbenzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dion,
(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-dion,
(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-dion,
(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-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-benzoxazol-5-yl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(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-dion,
(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-dion,
(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-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-propyl-8,8,12,16-tetramethyl-3-(2-methyl-benzoxazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-benzoxazol-5-yl)-10-propyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,11-dihydroxy-10-propyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-butyl-5,5,9,13-tetramethyl-16-(2-methylbenzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dion,
(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-dion,
(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-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-butyl-8,8,12,16-tetramethyl-3-(2-methyl-benzoxazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-benzoxazol-5-yl)-10-butyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,11-dihydroxy-10-butyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-allyl-5,5,9,13-tetramethyl-16-(2-methylbenzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dion,
(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-dion,
(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-dion,
(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-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-benzoxazol-5-yl)-10-allyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,11-dihydroxy-10-allyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(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-dion,
(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-dion,
(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-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-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-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-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-dion,
(1S,3S,7S,10R,11S,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-dion,
(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-dion,
(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-dion,
(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-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-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-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-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-dion,
(1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,11-dihydroxy-10-but-3-enyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dion,
(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-dion,
(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-dion,
(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-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-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-dion,
(1S,3S,7S,10R,11S,12S,16R)-7,11-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-dion,
(1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,11-dihydroxy-10-but-3-inyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dion.The compounds mentioned below are particularly preferred according to the invention as effector base bodies:
(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-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) -1-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 -thiazol-4-yl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(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] heptadecanes-5,9-dione,
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-thiazol-4-yl) -1-methylvinyl] -7,11-dihydroxy-8,8 , 10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-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] -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) -1-methyl-vinyl] -4,8-dihydroxy-7-ethyl -5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione,
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-methyl-2- (2 methyl-thiazol-4-yl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S (E), 7S, 10R, 11S, 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 [14.1.0] heptadecanes-5,9-dione,
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-thiazol-4-yl) -1-methylvinyl] -7,11-dihydroxy-10-ethyl -8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-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) -1-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] heptadecanes-5,9-dione,
(1S, 3S (Z), 7S, 10R, 11S, 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] heptadecanes-5,9-dione,
(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-thiazol-4-yl) -1-fluoro-vinyl] -7,11-dihydroxy-8 , 8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-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] -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) -1-chloro-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-chloro-2- (2-methyl -thiazol-4-yl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S (Z), 7S, 10R, 11S, 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] heptadecanes-5,9-dione,
(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-thiazol-4-yl) -1-chloro-vinyl] -7,11-dihydroxy-8 , 8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-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] -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) -1-fluoro-vinyl] -4,8-dihydroxy-7-ethyl -5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione,
(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-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] heptadecanes-5,9-dione,
(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-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] heptadecanes-5,9-dione,
(1S, 3S (Z), 7S, 10R, 11 S, 12S, 16R) -3- [2- (2-aminomethylthiazol-4-yl) -1-fluoro-vinyl] -7,11-dihydroxy- 10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-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) -1-chloro-vinyl] -4,8-dihydroxy-7-ethyl -5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione,
(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-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] heptadecanes-5,9-dione,
(1S, 3S (Z), 7S, 10R, 11S, 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] heptadecanes-5,9-dione,
(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-thiazol-4-yl) -1-chloro-vinyl] -7,11-dihydroxy-10 ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-methyl-2- (2-pyridyl) - vinyl] -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-pyridyl ) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-methyl-2- (2-pyridyl ) vinyl] -oxacyclohexadec-13-ene-2,6-dione,
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-methyl-2- (2 pyridyl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-fluoro-2- (2-pyridyl) - vinyl] -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-pyridyl ) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-chloro-2- (2-pyridyl) - vinyl] -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-chloro-2- (2-pyridyl ) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-fluoro-2- (2-pyridyl ) vinyl] -oxacyclohexadec-13-ene-2,6-dione,
(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-fluoro-2- (2 pyridyl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-chloro-2- (2-pyridyl ) vinyl] -oxacyclohexadec-13-ene-2,6-dione,
(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-chloro-2- (2 pyridyl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-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) -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) -1-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 oxazole-4-yl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- [2- (2-hydroxymethyl-oxazol-4-yl) -1-methyl-vinyl] -8 , 8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-oxazol-4-yl) -1-methylvinyl] -7,11-dihydroxy-8,8 , 10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-methyl-2- (2-methyl oxazole-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) -1-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) -1-methyl-vinyl] -4,8-dihydroxy-7-ethyl -5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione,
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-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] heptadecanes-5,9-dione,
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-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] heptadecanes-5,9-dione,
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-oxazol-4-yl) -1-methylvinyl] -7,11-dihydroxy-10-ethyl -8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-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) -1-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 oxazole-4-yl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- [2- (2-hydroxymethyl-oxazol-4-yl) -1-fluoro-vinyl] -8 , 8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-oxazol-4-yl) -1-fluoro-vinyl] -7,11-dihydroxy-8 , 8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-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) -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-oxazol-4-yl) -1-chloro-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-chloro-2- (2-methyl oxazole-4-yl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- [2- (2-hydroxymethyl-oxazol-4-yl) -1-chloro-vinyl] -8 , 8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-oxazol-4-yl) -1-chloro-vinyl] -7,11-dihydroxy-8 , 8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-fluoro-2- (2-methyl oxazole-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-l3-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,
(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-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] heptadecanes-5,9-dione,
(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- [2- (2-hydroxymethyl-oxazol-4-yl) -1-fluoro-vinyl] -10 ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-oxazol-4-yl) -1-fluoro-vinyl] -7,11-dihydroxy-10 ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-chloro-2- (2-methyl oxazole-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-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) -1-chloro-vinyl] -4,8-dihydroxy-7-ethyl -5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione,
(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-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] heptadecanes-5,9-dione,
(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-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] heptadecanes-5,9-dione,
(1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-oxazol-4-yl) -1-chloro-vinyl] -7,11-dihydroxy-10 ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecanes-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,
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-8,8,10,12,16-penta methyl-3- [2- (2-methyl-thiazol-4 -yl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethylthiazol-4-yl) vinyl] -8, 8.10 , 12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S (E), 7S, 10R, 11S, 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] heptadecanes-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,
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [2- (2-methyl-thiazol -4-yl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S (E), 7S, 10R, 11S, 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] heptadecanes-5,9-dione,
(1S, 3S (E), 7S, 10R, 11S, 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] heptadecanes-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,
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-8,8,10,12,16-penta methyl-3- [2- (2-pyridyl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecanes-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,
(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- (2- (2-pyridyl) - vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-5,5,7,9,13-pentamethyl-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) -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) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- (2-methyl-benzothiazol-5-yl) -4, 17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethyl-benzothiazol-5-yl) -8,8,10,12,16-pentamethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecanes-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,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) - 4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethyl-benzothiazol-5-yl) -10-ethyl-8,8,12,16-tetramethyl- 4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 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] heptadecanes-5,9-dione,
(4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-7-propyl-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-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,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-propyl-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) - 4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethyl-benzothiazol-5-yl) -10-propyl-8,8,12,16-tetramethyl- 4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 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] heptadecanes-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-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,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-l0-butyl-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) - 4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethyl-benzothiazol-5-yl) -10-butyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [ 14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-butyl-8,8,12,16-tetramethyl- 4,17-dioxa-bicyclo [14.1.0] heptadecanes-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-13 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,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-allyl-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) - 4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethyl-benzothiazol-5-yl) -10-allyl-8,8,12,16-tetramethyl- 4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-allyl-8,8,12,16-tetramethyl- 4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-7-prop-2-ynyl-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-ynyl-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-ynyl-5,5,9,13- tetramethyl-oxacyclohexadec-13-ene-2,6-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-prop-2-ynyl-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5 -yl) -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethyl-benzothiazol-5-yl) -10-prop-2-ynyl-8,8,12, 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-prop-2-ynyl-8,8,12, 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecanes-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-l3-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,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-but-3-enyl-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5 -yl) -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 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] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 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] heptadecanes-5,9-dione,
(4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-7-but-3-ynyl-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazolu-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-ynyl-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-ynyl-5,5,9,13- tetramethyl-oxacyclohexadec-13-ene-2,6-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-but-3-ynyl-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5 -yl) -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethyl-benzothiazol-5-yl) -10-but-3-ynyl-8,8,12, 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-but-3-ynyl-8,8,12, 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16- (2-methylbenzoxazol-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) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- (2-methyl-benzoxazol-5-yl) -4, 17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -8,8,10,12,16-pentamethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- (2-methylbenzoxazol-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] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -10-ethyl-8,8,12,16-tetramethyl- 4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl- 4,17-dioxa-bicyclo [14.1.0] heptadecanes-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,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-propyl-8,8,12,16-tetramethyl-3- (2-methyl-benzoxazol-5-yl) - 4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -10-propyl-8,8,12,16-tetramethyl- 4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-propyl-8,8,12,16-tetramethyl- 4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-7-butyl-5,5,9,13-tetramethyl-16- (2-methylbenzoxazol-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-10-butyl-8,8,12,16-tetramethyl-3- (2-methyl-benzoxazol-5-yl) - 4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -10-butyl-8,8,12,16-tetramethyl- 4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-butyl-8,8,12,16-tetramethyl- 4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-7-allyl-5,5,9,13-tetramethyl-16- (2-methylbenzoxazol-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] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -10-allyl-8,8,12,16-tetramethyl- 4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-allyl-8,8,12,16-tetramethyl- 4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-7-prop-2-ynyl-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-ynyl-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-ynyl-5,5,9,13- tetramethyl-oxacyclohexadec-13-ene-2,6-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-prop-2-ynyl-8,8,12,16-tetramethyl-3- (2-methyl-benzoxazol-5 -yl) -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -10-prop-2-ynyl-8,8,12, 16-tetramethyl-4,17-dioxa-bicyclo (14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-prop-2-ynyl-8,8,12, 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecanes-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,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-but-3-enyl-8,8,12,16-tetramethyl-3- (2-methyl-benzoxazol-5 -yl) -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -10-but-3-enyl-8,8,12, 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-but-3-enyl-8,8,12, 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-7-but-3-ynyl-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-ynyl-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-ynyl-5,5,9,13- tetramethyl-oxacyclohexadec-13-ene-2,6-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-but-3-ynyl-8,8,12,16-tetramethyl-3- (2-methyl-benzoxazol-5 -yl) -4.17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethyl-benzoxazol-5-yl) -10-but-3-ynyl-8,8,12, 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecanes-5,9-dione,
(1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-but-3-ynyl-8,8,12, 16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecanes-5,9-dione.

In einer erfindungsgemäßen Verbindung der allgemeinen Formel (1), enthaltend einen der obengenannten Grundkörper, sind die Wasserstoffatome in den obengenannten Grundkörpern an den in Formel (1) angegebenen Positionen durch Reste L1-L3 ersetzt, wobei die Reste L1-L3 die oben angegebenen Bedeutungen haben.In a compound of the general formula (1) according to the invention, containing one of the above-mentioned basic bodies, the hydrogen atoms in the above-mentioned basic bodies are replaced at the positions indicated in formula (1) by radicals L 1 -L 3 , the radicals L 1 -L 3 have the meanings given above.

Die Erfindung betrifft ferner Linker der allgemeinen Formel III1

Figure 00340001
worin
RG1 eine O=C=N-Gruppe oder eine S=C=N-Gruppe sein kann, und o, V, q und
FG1 die bereits oben genannten Bedeutungen haben,
sowie Linker der allgemeinen Formel III2
Figure 00340002
worin
RG2 eine Hal-C(=T)-CHR22-Gruppe oder eine Hal-C(=T)-CHR22-NR23-C(=T)-Gruppe oder eine R26-C(=O)-O-C(=T)-CHR22-Gruppe oder eine R26-C(=O)-O-C(=T)-CHR22-NR23-C(=T)-Gruppe sein kann, R26 C1-C10 Alkyl, Aryl, Aralkyl sein kann, und o, V, q, T und FG1 die bereits oben genannten Bedeutungen haben,
sowie Linker der allgemeinen Formel III3
Figure 00350001
worin
RG3 eine OH-Gruppe oder eine NHR24a-Gruppe oder eine COOH-Gruppe sein kann, und o, V, q und FG1 die bereits oben genannten Bedeutungen haben; jedoch mit der Bedingung, dass die Verbindung 1-(4-Amino-phenyl)-pyrrol-2,5-dion nicht umfasst ist.The invention further relates to linkers of the general formula III 1
Figure 00340001
wherein
RG 1 can be an O = C = N group or an S = C = N group, and o, V, q and
FG 1 have the meanings already mentioned,
and linkers of the general formula III 2
Figure 00340002
wherein
RG 2 is a Hal-C (= T) -CHR 22 group or a Hal-C (= T) -CHR 22 -NR 23 -C (= T) group or an R 26 -C (= O) -OC (= T) -CHR 22 group or an R 26 -C (= O) -OC (= T) -CHR 22 -NR 23 -C (= T) group, R 26 can be C 1 -C 10 alkyl , Aryl, aralkyl, and o, V, q, T and FG 1 have the meanings already mentioned,
and linkers of the general formula III 3
Figure 00350001
wherein
RG 3 can be an OH group or an NHR 24a group or a COOH group, and o, V, q and FG 1 have the meanings already mentioned above; however, provided that the compound 1- (4-aminophenyl) pyrrole-2,5-dione is not included.

Erfindungsgemäss besonders bevorzugt sind Linker der allgemeinen Formeln III1, III2 oder III3, wobei V eine Bindung oder einen Arylrest darstellt, o gleich Null ist und T ein Sauerstoffatom ist.Linkers of the general formulas III 1 , III 2 or III 3 are particularly preferred according to the invention, where V is a bond or an aryl radical, o is zero and T is an oxygen atom.

Die Erfindung betrifft ferner Verfahren,
einen Linker der allgemeinen Formel III1
mit einer Verbindung der allgemeinen Formel 1, worin die Bedingung, dass mindestens eine Gruppe L1, L2 oder L4 einen Linker darstellt, nicht erfüllt sein muss, und worin L1 und/oder L2 und/oder L4 die Bedeutung eines Wasserstoffatomes haben und freie, für die Umsetzung nicht benötigte Hydroxyl- und/oder Amino-Gruppen gegebenenfalls geschützt sind, umzusetzen,
einen Linker der allgemeinen Formel III2
mit einer Verbindung der allgemeinen Formel I, worin die Bedingung, dass mindestens eine Gruppe L1, L2 oder L4 einen Linker darstellt, nicht erfüllt sein muss, und L1 und/oder L2 und/oder L4 die Bedeutung eines Wasserstoffatomes haben und freie, für die Umsetzung nicht benötigte Hydroxyl- und/oder Amino-Gruppen gegebenenfalls geschützt sind, umzusetzen, oder
einen Linker der allgemeinen Formel III3
mit einer Verbindung der allgemeinen Formel 1, worin die Bedingung, dass mindestens eine Gruppe L1, L2 oder L4 einen Linker darstellt, nicht erfüllt sein muss, und L1 und/oder L2 und/oder L4 die Bedeutung einer C(=O)Hal-Gruppe oder einer C(=S)Hal-Gruppe haben und freie, für die Umsetzung nicht benötigte Hydroxyl- und/oder Amino-Gruppen gegebenenfalls geschützt sind, umzusetzen.The invention further relates to methods
a linker of the general formula III 1
with a compound of general formula 1, in which the condition that at least one group L 1 , L 2 or L 4 is a linker need not be met, and in which L 1 and / or L 2 and / or L 4 has the meaning of a Have a hydrogen atom and free hydroxyl and / or amino groups that are not required for the reaction are optionally protected,
a linker of the general formula III 2
with a compound of general formula I, in which the condition that at least one group L 1 , L 2 or L 4 is a linker need not be met, and L 1 and / or L 2 and / or L 4 has the meaning of a hydrogen atom have and, if necessary, free hydroxyl and / or amino groups which are not required for the reaction are protected, or
a linker of the general formula III 3
with a compound of general formula 1, in which the condition that at least one group L 1 , L 2 or L 4 is a linker need not be met, and L 1 and / or L 2 and / or L 4 has the meaning of a C. (= O) Hal group or a C (= S) Hal group and free hydroxyl and / or amino groups that are not required for the reaction are optionally protected.

Die Erfindung betrifft ferner die Verwendung einer Verbindung der allgemeinen Formel 1, wobei die Substituenten die oben genannten Bedeutungen haben, jedoch die Bedingung, dass mindestens ein Substituent L1, L2 oder L4 einen Linker der allgemeinen Formel III darstellt, nicht erfüllt sein muss, und mindestens ein Substituent L1, L2 oder L4 Wasserstoff, eine Gruppe C(=O)Cl, oder eine Gruppe C(S)Cl darstellt, in einem Verfahren wie oben beschrieben.The invention further relates to the use of a compound of general formula 1, where the substituents have the meanings given above, but the condition that at least one substituent ent L 1 , L 2 or L 4 represents a linker of the general formula III, need not be fulfilled, and at least one substituent L 1 , L 2 or L 4 is hydrogen, a group C (= O) Cl, or a group C ( S) represents Cl in a process as described above.

Die Erfindung betrifft ferner die Verwendung einer Verbindung der allgemeinen Formel 1, wobei die Substituenten die oben genannten Bedeutungen haben, jedoch die Bedingung, dass mindestens ein Substituent L1, L2 oder L4 einen Linker der allgemeinen Formel III darstellt, nicht erfüllt sein muss, und mindestens ein Substituent L1, L2 oder L4 Wasserstoff, eine Gruppe C(=O)Cl, oder eine Gruppe C(S)Cl darstellt, zur Herstellung eines Effektor-Erkennungseinheit-Konjugats wie oben beschrieben.The invention further relates to the use of a compound of the general formula 1, where the substituents have the meanings given above, but the condition that at least one substituent L 1 , L 2 or L 4 is a linker of the general formula III need not be met , and at least one substituent L 1 , L 2 or L 4 represents hydrogen, a group C (= O) Cl, or a group C (S) Cl, for producing an effector-recognition unit conjugate as described above.

Die Erfindung betrifft ferner die Verwendung eines Linkers der allgemeinen Formel III1, III2 oder III3 zur Herstellung eines Effektor-Konjugats, wie oben beschrieben.The invention further relates to the use of a linker of the general formula III 1 , III 2 or III 3 for the preparation of an effector conjugate, as described above.

Die Erfindung betrifft ferner die Verwendung eines Linkers der allgemeinen Formel III1, III2 oder III3 zur Herstellung eines Effektor-Erkennungseinheit-Konjugats wie oben beschrieben.The invention further relates to the use of a linker of the general formula III 1 , III 2 or III 3 for the production of an effector-recognition unit conjugate as described above.

Die Erfindung betrifft ferner die Verwendung einer Erkennungseinheit, wie vorstehend beschrieben, in einem der erfindungsgemäßen Verfahren zur Herstellung eines Eftektor-Erkennungseinheit-Konjugats, wie oben beschrieben.The invention further relates to the Use of a recognition unit as described above in one of the methods according to the invention for the preparation of an effector-recognition unit conjugate as above described.

Die Erfindung betrifft ferner die erfindungsgemäßen Effektor-Erkennungseinheit-Konjugate zur Verwendung als Medikament oder zur Herstellung eines Medikaments oder einer pharmazeutischen Zusammensetzung.The invention further relates to the effector recognition unit conjugates according to the invention for use as a medicament or for the manufacture of a medicament or an pharmaceutical composition.

Die Erfindung betrifft schließlich die Verwendung der erfindungsgemäßen Effektor-Erkennungseinheit-Konjugate zur Herstellung von Medikamenten für die Behandlung von Erkrankungen, die mit proliferativen Prozessen verknüpft sind, wie Tumore, entzündliche und/oder neurodegenerative Erkrankungen, Multiple Sklerose, Morbus Alzheimer, oder für die Behandlung von Angiogenese-assoziierten Erkrankungen, wie Tumorwachstum, rheumatoide Arthritis oder Erkrankungen des Augenhintergrundes.Finally, the invention relates to Use of the effector recognition unit conjugates according to the invention for the manufacture of medicines for the treatment of diseases, associated with proliferative processes, such as tumors, inflammatory and / or neurodegenerative diseases, multiple sclerosis, disease Alzheimer's, or for the treatment of angiogenesis-associated Diseases such as tumor growth, rheumatoid arthritis or illnesses of the fundus.

Beispiele zur Synthese von Linkern (L)Examples for the synthesis of Linkers (L)

Beispiel L1Example L1

(S) 2-[(3-Methyltrisulfanyl-propionyl)-methyl-amino]-propansäure (S) 2 - [(3-Methyltrisulfanyl-propionyl) methylamino] propanoic acid

Beispiel L1aExample L1a

(S) 2-[(3-Acetylsulfanyl-propionyl)-methyl-amino]-propansäure ethylester(S) 2 - [(3-Acetylsulfanyl-propionyl) methylamino] propanoic acid ethyl ester

Die Lösung von 15 g (89,5 mmol) N-Methylalaninethylester-Hydrochlorid in 850 ml wasserfreiem Tetrahydrofuran versetzt man bei 23°C mit 4,1 g einer ca. 60%igen Natriumhydrid-Dispersion und nach 3 Stunden mit 23,5 g 3-Acetylsulfanylpropansäurechlorid. Man lässt 2 Tage reagieren, versetzt mit gesättigter Natriumhydrogencarbonatlösung und extrahiert mehrfach mit Ethylacetat. Die vereinigten organischen Extrakte wäscht man mit gesättigter Natriumchloridlösung, trocknet über Natriumsulfat und reinigt den nach Filtration und Lösungsmittelabzug erhaltenen Rückstand durch Chromatographie an feinem Kieselgel. Isoliert werden 17,6 g (67,3 mmol, 75%) der Titelverbindung als farbloses Öl.The solution of 15 g (89.5 mmol) of N-methylalanine ethyl ester hydrochloride in 850 ml of anhydrous tetrahydrofuran, 4.1 is added at 23 ° C. g of an approximately 60% sodium hydride dispersion and after 3 hours with 23.5 g of 3-acetylsulfanylpropanoic acid chloride. You leave React for 2 days, mixed with saturated sodium bicarbonate solution and extracted several times with ethyl acetate. The united organic You wash extracts with saturated Sodium chloride solution, dries over Sodium sulfate and cleans the after filtration and removal of solvent residue obtained by chromatography on fine silica gel. 17.6 are isolated g (67.3 mmol, 75%) of the title compound as a colorless oil.

Beispiel L1bExample L1b

(S) 2-[(3-Mercapto-propionyl)-methyl-amino]-propansäure(S) 2 - [(3-mercapto-propionyl) methylamino] propanoic acid

Die Lösung von 17,6 g (67,3 mmol) der nach Beispiel L1a dargestellten Verbindung in 150 ml Methanol versetzt man bei 23°C mit 44 ml einer 5M Natronlauge und rührt 5 Stunden. Durch Zugabe einer 4N Salzsäure stellt man einen pH von 2 ein und extrahiert mit Dichlormethan. Die vereinigten organischen Extrakte wäscht man mit gesättigter Natriumchloridlösung und trocknet über Natriumsulfat. Den nach Filtration und Lösungsmittelabzug erhaltenen Rückstand (13,0 g, max. 67,3 mmol) setzt man ohne Reinigung weiter um.The solution of 17.6 g (67.3 mmol) the compound shown in Example L1a was added to 150 ml of methanol one at 23 ° C with 44 ml of a 5M sodium hydroxide solution and stirred for 5 hours. By encore a 4N hydrochloric acid a pH of 2 and extracted with dichloromethane. The United organic extracts are washed with saturated Sodium chloride solution and dries over Sodium sulfate. The one obtained after filtration and removal of solvent Residue (13.0 g, max. 67.3 mmol) is reacted further without purification.

Beispiel L1cExample L1c

(S) 2-[(3-Mercapto-propionyl)-methyl-amino]-propansäure methylester(S) 2 - [(3-Mercapto-propionyl) methylamino] propanoic acid methyl ester

Die Lösung von 4,53 g (max. 23,7 mmol) des nach Beispiel L1 b dargestellten Rohproduktes in 135 ml Diethylether verestert man bei 0°C mit einer etherischen Lösung von Diazomethan. Nach Lösungsmittelabzug isoliert man 4,59 g (22,4 mmol, 94%) der Titelverbindung als blass gelbes Öl, das man ohne Reinigung weiter umsetzt.The solution of 4.53 g (max. 23.7 mmol) of the crude product shown in Example L1 b in 135 ml of diethyl ether esterify at 0 ° C with an ethereal solution of diazomethane. Isolated after removal of solvent 4.59 g (22.4 mmol, 94%) of the title compound as a pale yellow oil, which one implemented without cleaning.

Beispiel L1dExample L1d

(S) 2-[(3-Methyltrisulfanyl-propionyl)-methyl-amino]-propansäure methylester(S) 2 - [(3-Methyltrisulfanyl-propionyl) methylamino] propanoic acid methyl ester

Zu der Lösung von 21 g 2-Methyldisulfanyl-isoindol-1,3-dion in 420 ml Trichlormethan gibt man die Lösung von 14 g (68,2 mmol) der nach Beispiel L1c dargestellten Verbindung in 180 ml Trichlormethan und rührt 16 Stunden bei 23°C. Man engt ein, nimmt in Dichlormethan auf und rührt 0,5 Stunden. Feststoff wird abfiltriert, das Filtrat eingeengt und der Rückstand durch Chromatographie an feinem Kieselgel gereinigt. Isoliert werden 16,2 g (57,2 mmol, 84%) der Titelverbindung als farbloses Öl.To the solution of 21 g of 2-methyldisulfanyl-isoindole-1,3-dione in 420 ml of trichloromethane, the solution of 14 g (68.2 mmol) is added compound shown in Example L1c in 180 ml of trichloromethane and stir 16 Hours at 23 ° C. The mixture is concentrated, taken up in dichloromethane and stirred for 0.5 hours. solid fuel is filtered off, the filtrate is concentrated and the residue purified by chromatography on fine silica gel. 16.2 are isolated g (57.2 mmol, 84%) of the title compound as a colorless oil.

Beispiel L1Example L1

(S) 2-[(3-Methyltrisulfanyl-propionyl)-methyl-amino]-propansäure(S) 2 - [(3-Methyltrisulfanyl-propionyl) methylamino] propanoic acid

Die Lösung von 10 g (35,3 mmol) der nach Beispiel L1d dargestellten Verbindung in 20 ml Ethanol versetzt man mit 1 l pH 7 Phosphatpuffer, Schweineleberesterase und inkubiert bei 27°C 46 Stunden. Durch Zugabe einer 4N Salzsäure stellt man auf pH 1 ein, extrahiert mit Dichlormethan, trocknet über Natriumsulfat und isoliert nach Filtration und Lösungsmittelabzug 8,3 g (30,8 mmol, 87%) der Titelverbindungn als farbloses Öl, das ohne weitere Reinigung umgesetzt wird.
1H-NMR (CDCl3): 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 (1H), 7,90 (1H) ppm.The solution of 10 g (35.3 mmol) of the compound shown in Example L1d in 20 ml of ethanol is mixed with 1 l of pH 7 phosphate buffer, pork liver esterase and incubated at 27 ° C. for 46 hours. By adding a 4N hydrochloric acid, the pH is adjusted to 1, 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 are isolated as a colorless oil, which is reacted without further purification ,
1 H-NMR (CDCl 3 ): 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 (1H), 7.90 (1H) ppm.

Beispiel L2Example L2

[(3-Methyltrisulfanyl-propionyl)-methyl-amino]-essigsäure[(3-Methyltrisulfanyl-propionyl) -methyl-amino] -acetic acid

Beispiel L2aExample L2a

2-[(3-Acetylsulfanyl-propionyl)-methyl-amino]-essigsäure ethylester2 - [(3-Acetylsulfanyl-propionyl) methylamino] acetic acid ethyl ester

7,13 g (46,4 mmol) N-Methylglycinethylester-Hydrochlorid setzt man in Analogie zu Beispiel L1a um und isoliert 6,9 g (27,9 mmol, 60%) der Titelverbindung als farbloses Öl.7.13 g (46.4 mmol) of N-methylglycine ethyl ester hydrochloride is reacted analogously to Example L1a and isolated 6.9 g (27.9 mmol, 60%) of the title compound as a colorless oil.

Beispiel L2bExample L2b

[(3-Mercapto-propionyl)-methyl-amino]-essigsäure[(3-Mercapto-propionyl) -methyl-amino] -acetic acid

7,6 g (30,7 mmol) der nach Beispiel L2a dargestellten Verbindung setzt man in Analogie zu Beispiel L1 b um und isoliert 4,92 g (27,8 mmol, 90%) der Titelverbindung als farbloses Öl.7.6 g (30.7 mmol) of that according to Example L2a shown connection is set in analogy to example L1 b um and isolated 4.92 g (27.8 mmol, 90%) of the title compound as colorless oil.

Beispiel L2cExample L2c

[(3-Mercapto-propionyl)-methyl-amino]-essigsäure methylester[(3-Mercapto-propionyl) methylamino] acetic acid methyl ester

4,92 g (27,8 mmol) der nach Beispiel L2b dargestellten Verbindung setzt man in Analogie zu Beispiel L1c um und isoliert 5,01 g (26,2 mmol, 94%) der Titelverbindung als farbloses Öl.4.92 g (27.8 mmol) according to the example L2b shown connection is set in analogy to example L1c um and isolated 5.01 g (26.2 mmol, 94%) of the title compound as colorless oil.

Beispiel L2dExample L2d

[(3-Methyltrisulfanyl-propionyl)-methyl-amino]-essigsäure methylester[(3-Methyltrisulfanyl-propionyl) methylamino] acetic acid methyl ester

2,00 g (10,5 mmol) der nach Beispiel L2c dargestellten Verbindung setzt man in Analogie zu Beispiel L1d um und isoliert 2,33 g (8,65 mmol, 82%) der Titelverbindung als farbloses Öl.2.00 g (10.5 mmol) of that from Example L2c shown connection is set in analogy to example L1d um and isolated 2.33 g (8.65 mmol, 82%) of the title compound as colorless oil.

Beispiel L2Example L2

[(3-Methyltrisulfanyl-propionyl)-methyl-amino]-essigsäure[(3-Methyltrisulfanyl-propionyl) -methyl-amino] -acetic acid

2,00 g (7,83 mmol) der nach Beispiel L2d dargestellten Verbindung setzt man in Analogie zu Beispiel L1 um und isoliert 0,64 g (2,51 mmol, 32%) der Titelverbindung als farbloses Öl.
1H-NMR (CDCl3): δ = 2,41 + 2,56 (3H), 2,61-3,27 (7H), 3,98 (2H), 4,38 (1H) ppm.2.00 g (7.83 mmol) of the compound shown in Example L2d is reacted analogously to Example L1 and 0.64 g (2.51 mmol, 32%) of the title compound is isolated as a colorless oil.
1 H NMR (CDCl 3 ): δ = 2.41 + 2.56 (3H), 2.61-3.27 (7H), 3.98 (2H), 4.38 (1H) ppm.

Beispiel L3Example L3

(S) 2-[(3-Methyltrisulfanyl-propionyl)-methyl-amino]-3-phenyl-propionsäure(S) 2 - [(3-Methyltrisulfanyl-propionyl) methylamino] -3-phenyl-propionic acid

Beispiel L3aExample L3a

(S) 2-[(3-Acetylsulfanyl-propionyl)-methyl-amino]-3-phenyl-propansäure ethylester(S) 2 - [(3-Acetylsulfanyl-propionyl) methylamino] -3-phenyl-propanoic acid, ethyl ester

7,73 g (31,7 mmol) N-Methylphenylalaninethylester-Hydrochlorid setzt man in Analogie zu Beispiel L1a um und isoliert 2,3 g (6,82 mmol, 22%) der Titelverbindung als farbloses Öl.7.73 g (31.7 mmol) of N-methylphenylalanine ethyl ester hydrochloride is reacted in analogy to example L1a and 2.3 g (6.82 mmol, 22%) of the title compound as a colorless oil.

Beispiel L3bExample L3b

(S) 2-[(3-Mercapto-propionyl)-methyl-amino]-3-phenyl-propansäure(S) 2 - [(3-mercapto-propionyl) methylamino] -3-phenyl-propanoic acid

1,09 g (3,23 mmol) der nach Beispiel L3a dargestellten Verbindung setzt man in Analogie zu Beispiel L1 b um und isoliert 0,744 g (2,78 mmol, 86%) der Titelverbindung als farbloses Öl.1.09 g (3.23 mmol) of that from Example L3a shown connection is set in analogy to example L1 b um and isolated 0.744 g (2.78 mmol, 86%) of the title compound as colorless oil.

Beispiel L3cExample L3c

(S) 2-[(3-Mercapto-propionyl)-methyl-amino]-3-phenyl-propansäure methylester(S) 2 - [(3-Mercapto-propionyl) methylamino] -3-phenylpropanoic acid methyl ester

0,74 g (2,77 mmol) der nach Beispiel L3b dargestellten Verbindung setzt man in Analogie zu Beispiel L1c um und isoliert 0,77 g (2,74 mmol, 99%) der Titelverbindung als farbloses Öl.0.74 g (2.77 mmol) of that from Example L3b shown connection is set in analogy to example L1c um and isolated 0.77 g (2.74 mmol, 99%) of the title compound as colorless oil.

Beispiel L3Example L3

(S) 2-[(3-Methyltrisulfanyl-propionyl)-methyl-amino]-3-phenyl-propansäure methylester(S) 2 - [(3-Methyltrisulfanyl-propionyl) methylamino] -3-phenylpropanoic acid methyl ester

0,77 g (2,74 mmol) der nach Beispiel L3c dargestellten Verbindung setzt man in Analogie zu Beispiel L1d um und isoliert 0,72 g (2,00 mmol, 73%) der Titelverbindung als farbloses Öl.0.77 g (2.74 mmol) according to the example L3c shown connection is set in analogy to example L1d um and isolated 0.72 g (2.00 mmol, 73%) of the title compound as colorless oil.

Beispiel L3Example L3

(S) 2-[(3-Methyltrisulfanyl-propionyl)-methyl-amino]-3-phenyl-propansäure(S) 2 - [(3-Methyltrisulfanyl-propionyl) methylamino] -3-phenyl-propanoic acid

0,72 g (2,00 mmol) der nach Beispiel L3d dargestellten Verbindung setzt man in Analogie zu Beispiel L1 um und isoliert 0,49 g (1,42 mmol, 71%) der Titelverbindung als farbloses Öl.0.72 g (2.00 mmol) of that from Example L3d shown connection is set in analogy to example L1 um and isolated 0.49 g (1.42 mmol, 71%) of the title compound as colorless oil.

Beispiel L4Example L4

4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-butansäure4- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) butanoic acid

20,0 g (193,9 mmol) 4-Aminobuttersäure versetzt man mit 19 g Maleinsäureanhydrid, 290 ml Essigsäure und erhitzt 4 Stunden im 130°C heissen Ölbad. Man engt unter wiederholtem Zusatz von Toluol azeotrop ein, nimmt den Rückstand in Dichlormethan auf und reinigt durch Chromatographie an feinem Kieselgel. Isoliert werden 17,1 g (93,4 mmol, 48%) der Titelverbindung als kristallinen Feststoff.
1H-NMR (CDCl3): δ = 1,93 (2H), 2,38 (2H), 3,60 (2H), 6,71 (2H) ppm.20.0 g (193.9 mmol) of 4-aminobutyric acid are mixed with 19 g of maleic anhydride, 290 ml of acetic acid and heated in an oil bath at 130 ° C. for 4 hours. The mixture is concentrated azeotropically with repeated addition of toluene, the residue is taken up in dichloromethane and purified by chromatography on fine silica gel. 17.1 g (93.4 mmol, 48%) of the title compound are isolated as a crystalline solid.
1 H NMR (CDCl 3 ): δ = 1.93 (2H), 2.38 (2H), 3.60 (2H), 6.71 (2H) ppm.

Beispiel L4aExample L4a

1-(3-Isocyanato-propyl)-pyrrol-2,5-dion1- (3-Isocyanato-propyl) -pyrrole-2,5-dione

5,0 g (27,3 mmol) der nach Beispiel L4 dargestellten Verbindung löst man in 90 ml Tetrahydrofuran, versetzt mit 8 ml Triethylamin, 6,17 ml Phosphorsäurediphenylesterazid und rührt 1,5 Stunden bei 23°C. Anschließend versetzt man mit 110 ml Toluol, destilliert das Tetrahydrofuran ab und erwärmt 2 Stunden auf 70°C. Das Rohprodukt reinigt man durch Chromatographie an feinem Kieselgel. Isoliert werden 1,77 g (9,82 mmol, 36%) der Titelverbindung.5.0 g (27.3 mmol) of that from Example L4 shown disconnects in 90 ml of tetrahydrofuran, mixed with 8 ml of triethylamine, 6.17 ml of phosphoric acid diphenyl ester azide and moves 1.5 hours at 23 ° C. Subsequently 110 ml of toluene are added and the tetrahydrofuran is distilled and warmed up 2 hours at 70 ° C. The The crude product is purified by chromatography on fine silica gel. 1.77 g (9.82 mmol, 36%) of the title compound are isolated.

Beispiel L5Example L5

6-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-hexansäure6- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -hexanoic acid

100 g (762 mmol) 6-Aminocapronsäure setzt man in Analogie zu Beispiel L5 um und isoliert 93,8 g (444 mmol, 58%) der Titelverbindung als kristallinen Feststoff.
1H-NMR (CDCl3): δ = 1,34 (2H), 1,55-1,70 (4H), 2,34 (2H), 3,51 (2H), 6,69 (2H) ppm.100 g (762 mmol) of 6-aminocaproic acid are reacted analogously to Example L5 and 93.8 g (444 mmol, 58%) of the title compound are isolated as a crystalline solid.
1 H NMR (CDCl 3 ): δ = 1.34 (2H), 1.55-1.70 (4H), 2.34 (2H), 3.51 (2H), 6.69 (2H) ppm ,

Beispiel L5aExample L5a

1-(5-Isocyanato-pentyl)-pyrrol-2,5-dion1- (5-Isocyanato-pentyl) -pyrrole-2,5-dione

10,0 g (47,3 mmol) der nach Beispiel L5 dargestellten Verbindung setzt man in Analogie zu Beispiel L4a um und isoliert 3,19 g (15,3 mmol, 32%) der Titelverbindung als farbloses Öl.10.0 g (47.3 mmol) of that according to Example L5 shown connection is set in analogy to example L4a um and isolated 3.19 g (15.3 mmol, 32%) of the title compound as colorless oil.

Beispiel L6Example L6

11-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-undecansäure11- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) undecanoic acid

10 g (49,7 mmol) 11-Aminoundecansäure setzt man in Analogie zu Beispiel L5 um und isoliert 6,29 g (22,4 mmol, 45%) der Titelverbindung als kristallinen Feststoff.
1H-NMR (CDCl3): δ = 1,19–1,36 (12H), 1,51-1,67 (4H), 2,34 (2H), 3,49 (2H), 6,68 (2H) ppm.10 g (49.7 mmol) of 11-aminoundecanoic acid are reacted analogously to Example L5 and 6.29 g (22.4 mmol, 45%) of the title compound are isolated as a crystalline solid.
1 H NMR (CDCl 3 ): δ = 1.19-1.36 (12H), 1.51-1.67 (4H), 2.34 (2H), 3.49 (2H), 6.68 (2H) ppm.

Beispiel L6aExample L6a

1-(10-Isocyanato-decyl)-pyrrol-2,5-dion1- (10-Isocyanato-decyl) -pyrrole-2,5-dione

5,28 g (18,8 mmol) der nach Beispiel L6 dargestellten Verbindung setzt man in Analogie zu Beispiel L4a um und isoliert 3,37 g (12,1 mmol, 64%) der Titelverbindung als farbloses Öl.5.28 g (18.8 mmol) according to the example L6 shown connection is set in analogy to example L4a um and isolated 3.37 g (12.1 mmol, 64%) of the title compound as colorless oil.

Beispiel L7Example L7

1-(4-Amino-phenyl)-pyrrol-2,5-dion1- (4-Amino-phenyl) -pyrrole-2,5-dione

Die Lösung von 21,6 g (200 mmol) 1,4-Phenylendiamin in 200 ml Tetrahydrofuran versetzt man über 1,5 Stunden mit der Lösung von 19,6 g Maleinsäureanhydrid und rührt 22 Stunden bei 23°C. Man filtriert, wäscht mit Tetrahydrofuran nach und trocknet das Filtrat. Isoliert werden 37,1 g (197 mmol, 98%) der Titelverbindung als kristalliner Feststoff.
1H-NMR (d6-DMSO): δ = 6,28 (1H), 6,48 (1H), 6,53 (2H), 7,30 (2H), 7,50–9,00 (2H) ppm.The solution of 21.6 g (200 mmol) of 1,4-phenylenediamine in 200 ml of tetrahydrofuran is mixed with the solution of 19.6 g of maleic anhydride over 1.5 hours and stirred at 23 ° C. for 22 hours. It is filtered, washed with tetrahydrofuran and the filtrate is dried. 37.1 g (197 mmol, 98%) of the title compound are isolated as a crystalline solid.
1 H NMR (d6-DMSO): δ = 6.28 (1H), 6.48 (1H), 6.53 (2H), 7.30 (2H), 7.50-9.00 (2H) ppm.

Beispiel L8Example L8

1-(4-Hydroxy-phenyl)-pyrrol-2,5-dion1- (4-Hydroxy-phenyl) -pyrrole-2,5-dione

Die Suspension aus 5,0 g (45,8 mmol) 4-Aminophenol, 4,49 g Maleinsäureanhydrid und 40 ml Essigsäure erhitzt man 3 Stunden unter Rückfluss. Man engt ein, entfernt restliche Essigsäure azeotrop durch wiederholte Destillation mit Essigsäure und reinigt den Rückstand durch Chromatographie an feinem Kieselgel. Isoliert werden 2,83 g (15,0 mmol, 33%) der Titelverbindung.
1H-NMR (d6-DMSO): δ = 6,83 (2H), 7,09 (2H), 7,13 (2H), 9,71 (1H) ppm.The suspension of 5.0 g (45.8 mmol) of 4-aminophenol, 4.49 g of maleic anhydride and 40 ml of acetic acid is heated under reflux for 3 hours. The mixture is concentrated, 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 are isolated.
1 H NMR (d6-DMSO): δ = 6.83 (2H), 7.09 (2H), 7.13 (2H), 9.71 (1H) ppm.

Beispiele zur Synthese von Effektor-Linker-Konjugaten (EL)Examples for the synthesis of Effector-Linker Conjugates (EL)

Beispiel EL1Example EL1

(4S,7R,8S,9S,13Z,16S)-[3-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-propyl]carbaminsäure-7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yl ester(4S, 7R, 8S, 9S, 13Z, 16S) - [3- (2,5-dioxo-2,5-dihydro-pyrrol-1-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

Beispiel EL1aExample EL1a

(4S,7R,8S,9S,13Z,16S)-7-Allyl-8-(terf-butyl-dimethyl-silanyloxy)-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-oxacyclohexadec-13-en-2,6-dion(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

Die Lösung von 6,0 g (7,93 mmol) (4S,7R,8S,9S,13Z,16S)-7-Allyl-4,8-bis(terfbutyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)oxacyclohexadec-13-en-2,6-dion, das man in Analogie zu dem in WO 00/66589 beschrieben Verfahren hergestellt hat, in 186 ml wasserfreiem Dichlormethan versetzt man bei 0°C mit 26,4 ml einer 20%igen Lösung von Trifluoressigsäure in Dichlormethan und rührt 6 Stunden bei 0°C. Man gießt in gesättigte Natriumhydrogencarbonatlösung, extrahiert mit Dichlormethan, wäscht die vereinigten organischen Extrakte mit Wasser und trocknet über Magnesiumsulfat. Den nach Filtration und Lösungsmittelabzug erhaltenen Rückstand reinigt man durch Chromatographie an feinem Kieselgel. Isoliert werden 3,32 g (5,17 mmol, 65%) der Titelverbindung als farbloser Feststoff.
1H-NMR (CDCl3): 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 (1H), 2,31-2,56 (6H), 2,83 (3H), 2,87 (1H), 3,00 (1H), 3,30 (1H), 3,90 (1H), 4,09 (1H), 4,94-5,03 (2H), 5,20 (1H), 5,77 (1H), 5,88 (1H), 7,34 (1H), 7,78 (1H), 7,95 (1H) ppm.The solution of 6.0 g (7.93 mmol) (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-4,8-bis (terfbutyl-dimethyl-silanyloxy) -5,5,9, 13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) oxacyclohexadec-13-en-2,6-dione, which was prepared in analogy to the process described in WO 00/66589, in 186 ml of anhydrous dichloromethane 26.4 ml of a 20% strength solution of trifluoroacetic acid in dichloromethane are added at 0 ° C. and the mixture is stirred at 0 ° C. for 6 hours. 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 obtained after filtration and removal of solvent is purified by chromatography on fine silica gel. 3.32 g (5.17 mmol, 65%) of the title compound are isolated as a colorless solid.
1H NMR (CDCl 3 ): 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 (1H), 2.31-2.56 (6H), 2.83 (3H), 2.87 (1H ), 3.00 (1H), 3.30 (1H), 3.90 (1H), 4.09 (1H), 4.94-5.03 (2H), 5.20 (1H), 5, 77 (1H), 5.88 (1H), 7.34 (1H), 7.78 (1H), 7.95 (1H) ppm.

Beispiel EL1bExample EL1b

(4S,7R,8S,9S,13Z,16S)-3-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-propyl]-carbaminsäure-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(4S, 7R, 8S, 9S, 13Z, 16S) -3- (2,5-dioxo-2,5-dihydro-pyrrol-1-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) der nach Beispiel EL1a dargestellten Verbindung löst man in einem Gemisch aus 1,5 ml Trichlormethan und 1,5 ml Dimethylformamid, versetzt mit 144 mg des nach Beispiel L4a dargestellten Linkers, 79 mg Kupfer-(I)-Chlorid und erhitzt 18 Stunden auf 70°C. Das Rohgemisch reinigt man durch Chromatographie an Dünnschichtplatten und isoliert 51 mg (62 μmol, 80%) der Titelverbindung als farbloses Öl.50 mg (78 μmol) of that according to Example EL1a shown connection triggers in a mixture of 1.5 ml trichloromethane and 1.5 ml dimethylformamide, mixed with 144 mg of the linker shown in Example L4a, 79 mg copper (I) chloride and heated at 70 ° C for 18 hours. The raw mix is purified by chromatography on thin-layer plates and isolated 51 mg (62 μmol, 80%) of the title compound as a colorless oil.

Beispiel EL1Example EL1

(4S,7R,8S,9S,13Z,16S)-[3-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-propyl]-carbaminsäure-7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yl ester(4S, 7R, 8S, 9S, 13Z, 16S) - [3- (2,5-dioxo-2,5-dihydro-pyrrol-1-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

Die Lösung von 41 mg (50 μmol) der nach Beispiel 1b dargestellten Verbindung in einem Gemisch aus 0,8 ml Tetrahydrofuran und 0,8 ml Acetonitril versetzt man 310 μl Hexafluorkieselsäure, 310 μl Fluorwasserstoff-Pyridin-Komplex und rührt 23 Stunden bei 23°C. Man gießt in eine 5%ige Natronlauge, extrahiert mit Ethylacetat, wäscht die vereinigten organischen Extrakte mit einer gesättigten Natriumchloridlösung und trocknet über Natriumsulfat. Den nach Filtration und Lösungsmittelabzug erhaltenen Rückstand reinigt man durch Chromatographie an Dünnschichtplatten und isoliert 26 mg (36,7 μmol, 73%) der Titelverbindung als farblosen Schaum.
1H-NMR (CDCl3): 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 (1 H), 2,28–3,02 (9H), 2,83 (3H), 3,31 (1H), 3,45 (1H), 3,68 (1H), 4,44+4,83 (1H), 4,99 (1H), 5,03 (1H), 5,15 (1H), 5,61 (1H), 5,72 (1H), 5,91 (1H), 6,68 (2H), 7,36 (1H), 7,78 (1H), 7,90 (1H) ppm.The solution of 41 mg (50 μmol) of the compound shown in Example 1b 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 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 obtained after filtration and removal of solvent is purified by chromatography on thin-layer plates and isolated 26 mg (36.7 μmol, 73%) of the title compound as a colorless foam.
1 H NMR (CDCl 3 ): 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 (1H), 2.28-3.02 (9H), 2.83 (3H), 3.31 (1H), 3.45 (1H) , 3.68 (1H), 4.44 + 4.83 (1H), 4.99 (1H), 5.03 (1H), 5.15 (1H), 5.61 (1H), 5.72 (1H), 5.91 (1H), 6.68 (2H), 7.36 (1H), 7.78 (1H), 7.90 (1H) ppm.

Beispiel EL2Example EL2

(1S,3S,7S,10R,11 S,12S,16R)-[3-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-propyl]-carbaminsäure-10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methylbenzothiazol-5-yl)-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-7-yl ester (A) und(1S, 3S, 7S, 10R, 11 S, 12S, 16R) - [3- (2,5-Dioxo-2,5-dihydro-pyrrol-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-dioxabicyclo [14.1.0] heptadec-7-yl ester (A) and

(1R,3S,7S,10R,11S,12S,16S)-[3-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-propyl]-carbaminsäure-10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methylbenzothiazol-5-yl)-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-7-yl ester (B)(1R, 3S, 7S, 10R, 11S, 12S, 16S) - [3- (2,5-dioxo-2,5-dihydro-pyrrol-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-dioxabicyclo [14.1.0] heptadec-7-yl ester (B)

Die Lösung von 44 mg (62,2 μmol) der nach Beispiel 1 dargestellten Verbindung in 2,0 ml Dichlormethan kühlt man auf -50°C und versetzt portionsweise über einen Zeitraum von 1,5 Stunden mit insgesamt 1,7 ml einer ca. 0,1 M Lösung von Dimethyldioxiran in Aceton. Man gießt in eine gesättigte Natriumthiosulfatlösung, extrahiert mit Dichlormethan und trocknet die vereinigten organischen Extrakte über Natriumsulfat. Den nach Filtration und Lösungsmittelabzug erhaltenen Rückstand reinigt man durch Chromatographie an Dünnschichtplatten und isoliert 22,7 mg (31,4 μmol, 50%) der Titelverbindung A sowie 7,6 mg (10,5 μmol, 17%) der Titelverbindung B jeweils als farblosen Schaum.
1H-NMR (CDCl3) von 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 (1H), 2,84 (3H), 3,30 (2H), 3,48 (2H), 3,68 (1H), 4,36+4,93 (1H), 4,99 (1H), 5,04 (1H), 5,54 (1H), 5,69 (1H), 6,05 (1H), 6,68 (2H), 7,32 (1H), 7,80 (1H), 7,88 (1 H) ppm.
1H-NMR (CDCl3) von B: δ = 1,02 (6H), 1,26 (3H), 1,33 (1H), 1,23–2,27 (12H), 2,54-2,78 (4H), 2,82 (3H), 2,91 (1H), 3,13 (1H), 3,40 (2H), 3,66 (1H), 4,11 (1H), 4,84 (1H), 4,95 (1H), 5,01 (1H), 5,70 (1H), 5,81+5,93 (1H), 6,04+6,13 (1H), 6,69 (2H), 7,35 (1H), 7,75 (1H), 7,90+7,99 (1H) ppm.The solution of 44 mg (62.2 μmol) of the compound shown in Example 1 in 2.0 ml of dichloromethane is cooled to -50 ° C. and a total of 1.7 ml of an approx. 0.1 M solution of dimethyldioxirane 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 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 the title compound A and 7.6 mg (10.5 μmol, 17%) of the title compound B are each isolated as colorless foam.
1 H NMR (CDCl 3 ) 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 (1H), 2.84 (3H), 3.30 (2H), 3.48 (2H), 3.68 (1H), 4, 36 + 4.93 (1H), 4.99 (1H), 5.04 (1H), 5.54 (1H), 5.69 (1H), 6.05 (1H), 6.68 (2H) , 7.32 (1H), 7.80 (1H), 7.88 (1H) ppm.
1 H NMR (CDCl 3 ) of B: δ = 1.02 (6H), 1.26 (3H), 1.33 (1H), 1.23-2.27 (12H), 2.54-2 , 78 (4H), 2.82 (3H), 2.91 (1H), 3.13 (1H), 3.40 (2H), 3.66 (1H), 4.11 (1H), 4, 84 (1H), 4.95 (1H), 5.01 (1H), 5.70 (1H), 5.81 + 5.93 (1H), 6.04 + 6.13 (1H), 6, 69 (2H), 7.35 (1H), 7.75 (1H), 7.90 + 7.99 (1H) ppm.

Beispiel EL3Example EL3

(4S,7R,8S,9S,13Z,16S)-[5-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-pentyl]-carbaminsäure-7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yl ester(4S, 7R, 8S, 9S, 13Z, 16S) - [5- (2,5-dioxo-2,5-dihydro-pyrrol-1-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

Beispiel EL3aExample EL3a

(4S,7R,8S,9S,13Z,16S)-[5-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-pentyl]-carbaminsäure-7-allyl-8-tert-butyl-dimethylsilyloxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-l3-en-4-yl ester(4S, 7R, 8S, 9S, 13Z, 16S) - [5- (2,5-dioxo-2,5-dihydro-pyrrol-1-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-I3-en-4-yl ester

50 mg (78 μmol) der nach Beispiel EL1a dargestellten Verbindung setzt man in Analogie zu Beispiel EL1b mit dem nach Beispiel L5a hergestellten Linker um und isoliert nach Reinigung 39 mg (45,9 μmol, 59%) der Titelverbindung als farbloses Öl.50 mg (78 μmol) of that according to Example EL1a shown connection is set in analogy to example EL1b around with the linker prepared according to example L5a and isolated after Purification 39 mg (45.9 μmol, 59%) of the title compound as a colorless oil.

Beispiel EL3Example EL3

(4S,7R,8S,9S,13Z,16S)-[5-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-pentyl]-carbaminsäure-7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yl ester(4S, 7R, 8S, 9S, 13Z, 16S) - [5- (2,5-dioxo-2,5-dihydro-pyrrol-1-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) der nach Beispiel EL3a dargestellten Verbindung setzt man in Analogie zu Beispiel EL1 um und isoliert nach Reinigung 43 mg (58,4 μmol, 59%) der Titelverbindung als farblosen Schaum.
1H-NMR (CDCl3): 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 (1H), 3,65 (1H), 4,41 + 4,53 (1H), 4,98 (1H), 5,03 (1H), 5,15 (1H), 5,60 (1H), 5,71 (1H), 5,90 (1H), 6,68 (2H), 7,35 (1H), 7,77 (1H), 7,89 + 7,96 (1H) ppm.84 mg (98.8 μmol) of the compound shown in Example EL3a is reacted analogously to Example EL1 and, after purification, 43 mg (58.4 μmol, 59%) of the title compound is isolated as a colorless foam.
1 H NMR (CDCl 3 ): 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 (1H), 3.65 (1H), 4.41 + 4.53 (1H), 4.98 (1H), 5.03 (1H), 5.15 (1H), 5.60 (1H), 5.71 (1H), 5.90 (1H), 6.68 (2H), 7.35 (1H), 7.77 (1H), 7 , 89 + 7.96 (1H) ppm.

Beispiel EL4Example EL4

(1S,3S,7S,10R,11S,12S,16R)-[5-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-pentyl]-carbaminsäure-10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methylbenzothiazol-5-yl)-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-7-yl ester (A) und(1S, 3S, 7S, 10R, 11S, 12S, 16R) - [5- (2,5-dioxo-2,5-dihydro-pyrrol-1-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

1R,3S,7S,10R,11S,12S,16S)-[5-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-pentyl]-carbaminsäure-10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methylbenzothiazol-5-yl)-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-7-yl ester (B)1R, 3S, 7S, 10R, 11S, 12S, 16S) - [5- (2,5-dioxo-2,5-dihydro-pyrrol-1-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) der nach Beispiel EL3 dargestellten Verbindung setzt man in Analogie zu Beispiel EL2 um und isoliert nach Reinigung 9,1 mg (12,1 μmol, 34%) der Titelverbindung A sowie 3,0 mg (4,0 μmol, 11 %) der Titelverbindung B jeweils als farblosen Schaum.
1H-NMR (CDCl3) von 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 (1H), 3,66 (1H), 4,46 (1H), 4,99 (1H), 5,04 (1H), 5,54 (1H), 5,69 (1H), 6,06 (1H), 6,68 (2H), 7,33 (1H), 7,80
(1H), 7,89 (1H) ppm. 1H-NMR (CDCl3) von B: δ = 0,78-2,74 (23H), 1,01 (3H), 1,03 (3H), 1,33 (3H), 2,82 (3H), 2,91 (1H), 3,14 (1H), 3,39 (1H), 3,47 (2H), 3,67 (1H), 4,12 (1H), 4,49 (1H), 4,92-5,06 (2H), 5,53+5,80 (1H), 5,69 (1H), 6,11 (1H), 6,68 (2H), 7,34 (1H), 7,74+7,79 (1H), 7,89+8,02 (1H) ppm.26 mg (35.3 μmol) of the compound shown in Example EL3 are set in analogy to Example EL2 µm and, after purification, isolated 9.1 mg (12.1 μmol, 34%) of the title compound A and 3.0 mg (4.0 μmol, 11%) of the title compound B in each case as a colorless foam.
1 H NMR (CDCl 3 ) 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 (1H), 3.66 (1H), 4.46 (1H), 4, 99 (1H), 5.04 (1H), 5.54 (1H), 5.69 (1H), 6.06 (1H), 6.68 (2H), 7.33 (1H), 7.80
(1H), 7.89 (1H) ppm. 1 H NMR (CDCl 3 ) of B: δ = 0.78-2.74 (23H), 1.01 (3H), 1.03 (3H), 1.33 (3H), 2.82 (3H ), 2.91 (1H), 3.14 (1H), 3.39 (1H), 3.47 (2H), 3.67 (1H), 4.12 (1H), 4.49 (1H) , 4.92-5.06 (2H), 5.53 + 5.80 (1H), 5.69 (1H), 6.11 (1H), 6.68 (2H), 7.34 (1H) , 7.74 + 7.79 (1H), 7.89 + 8.02 (1H) ppm.

Beispiel EL5Example EL5

(4S,7R,8S,9S,13Z,16S)-[10-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-decyl]-carbaminsäure-7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yl ester(4S, 7R, 8S, 9S, 13Z, 16S) - [10- (2,5-dioxo-2,5-dihydro-pyrrol-1-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

Beispiel EL5aExample EL5a

(4S,7R,8S,9S,13Z,16S)-[10-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-decyl]-carbaminsäure-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(4S, 7R, 8S, 9S, 13Z, 16S) - [10- (2,5-dioxo-2,5-dihydro-pyrrol-1-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) der nach Beispiel EL1a dargestellten Verbindung setzt man in Analogie zu Beispiel EL1 b mit dem nach Beispiel L6a hergestellten Linker um und isoliert nach Reinigung 56 mg (60,8 μmol, 78%) der Titelverbindung als farbloses Öl.50 mg (78 μmol) of that according to Example EL1a shown connection is set in analogy to example EL1 b around with the linker prepared according to example L6a and isolated after Purification 56 mg (60.8 μmol, 78%) of the title compound as a colorless oil.

Beispiel EL5Example EL5

(4S,7R,8S,9S,13Z,16S)-[10-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-decyl]-carbaminsäure-7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yl ester(4S, 7R, 8S, 9S, 13Z, 16S) - [10- (2,5-dioxo-2,5-dihydro-pyrrol-1-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) der nach Beispiel EL5a dargestellten Verbindung setzt man in Analogie zu Beispiel EL1 um und isoliert nach Reinigung 10 mg (12,4 μmol, 57%) der Titelverbindung als farblosen Schaum.
1H-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 (1H), 2,82 (3H), 2,96 (1H), 3,47 (1H), 3,50 (2H), 3,66 (1H), 3,97 + 4,36 (1H), 4,98 (1H), 5,04 (1H), 5,16 (1H), 5,61 (1H), 5,72 (1H), 5,91 (1H), 6,68 (2H), 7,37 (1H), 7,77 (1H), 7,90 + 7,97 (1H) ppm.20 mg (21.7 μmol) of the compound shown in Example EL5a is reacted analogously to Example EL1 and, after purification, 10 mg (12.4 μmol, 57%) of the title compound is isolated as a colorless foam.
1 H-NMR (CDCl 3 ): 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 (1H), 2.82 (3H), 2.96 (1H), 3.47 (1H), 3.50 (2H), 3.66 ( 1H), 3.97 + 4.36 (1H), 4.98 (1H), 5.04 (1H), 5.16 (1H), 5.61 (1H), 5.72 (1H), 5 , 91 (1H), 6.68 (2H), 7.37 (1H), 7.77 (1H), 7.90 + 7.97 (1H) ppm.

Beispiel EL6Example EL6

(1S,3S,7S,10R,11S,12S,16R)-[10-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-decyl]-carbaminsäure-10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methylbenzothiazol-5-yl)-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-7-yl ester (A) und(1S, 3S, 7S, 10R, 11S, 12S, 16R) - [10- (2,5-dioxo-2,5-dihydro-pyrrol-1-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

(1R,3S,7S,10R,11S,12S,16S)-[10-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-decyl]-carbaminsäure-10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methylbenzothiazol-5-yl)-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-7-yl ester (B)(1R, 3S, 7S, 10R, 11S, 12S, 16S) - [10- (2,5-dioxo-2,5-dihydro-pyrrol-1-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 (B)

18 mg (22 μmol) der nach Beispiel EL5 dargestellten Verbindung setzt man in Analogie zu Beispiel EL2 um und isoliert nach Reinigung 9,2 mg (11,2 μmol, 51 %) der Titelverbindung A sowie 3,2 mg (3,9 μmol, 18%) der Titelverbindung B jeweils als farblosen Schaum.
1H-NMR (CDCl3) von 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 (1H), 3,87 + 4,43 (1H), 4,98 (1H), 5,04 (1H), 5,53 (1H), 5,69 (1H), 6,07 (1H), 6,68 (2H), 7,33 (1H), 7,80 (1H), 7,89 + 7,93 (1H) ppm.
1H-NMR (CDCl3) von 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 (1H), 2,52-2,76 (4H), 2,81 (3H), 2,91 (1H), 3,40 (1H), 3,51 (2H), 3,67 + 3,82 (1H), 4,13 + 4,26 (1H), 4,46 (1H), 4,94 (1H), 5,01 (1H), 5,70 (1H), 5,81 + 5,94 (1H), 6,05 + 6,12 (1H), 6,68 (2H), 7,36 (1H), 7,74 (1H), 7,91 + 8,02 (1H) ppm.18 mg (22 μmol) of the compound shown in Example EL5 is reacted analogously to Example EL2 and, after purification, 9.2 mg (11.2 μmol, 51%) of the title compound A and 3.2 mg (3.9 μmol) are isolated , 18%) of the title compound B in each case as a colorless foam.
1 H NMR (CDCl 3 ) 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 (1H), 3.87 + 4 , 43 (1H), 4.98 (1H), 5.04 (1H), 5.53 (1H), 5.69 (1H), 6.07 (1H), 6.68 (2H), 7, 33 (1H), 7.80 (1H), 7.89 + 7.93 (1H) ppm.
1 H NMR (CDCl 3 ) 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 (1H), 2.52-2.76 (4H), 2.81 (3H), 2.91 (1H), 3 , 40 (1H), 3.51 (2H), 3.67 + 3.82 (1H), 4.13 + 4.26 (1H), 4.46 (1H), 4.94 (1H), 5 , 01 (1H), 5.70 (1H), 5.81 + 5.94 (1H), 6.05 + 6.12 (1H), 6.68 (2H), 7.36 (1H), 7 , 74 (1H), 7.91 + 8.02 (1H) ppm.

Beispiel EL7Example EL7

(4S,7R,8S,9S,13Z,16S)-[3-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-propyl]-carbaminsäure-7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yl ester(4S, 7R, 8S, 9S, 13Z, 16S) - [3- (2,5-dioxo-2,5-dihydro-pyrrol-1-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

Beispiel EL7aExample 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-en-2,6-dion(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

Die Lösung von 5,3 g (7,01 mmol) (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-en-2,6-dion, das man in Analogie zu dem in WO 00/66589 beschrieben Verfahren hergestellt hat, in einem Gemisch aus 85 ml Tetrahydrofuran und 85 ml Acetonitril versetzt man mit 31,7 ml Hexafluorkieselsäure, kühlt auf 0°C, tropft 8,1 ml Trifluoressigsäure zu und rührt 20 Stunden bei 0°C. Man gießt in Wasser, neutralisiert durch Zugabe einer gesättigten Natriumhydrogencarbonatlösung und extrahiert mehrfach mit Ethylacetat. Die vereinigten organischen Extrakte wäscht man mit gesättigter Natriumchloridlösung, trocknet über Natriumsulfat und reinigt den nach Filtration und Lösungsmittelabzug gewonnenen Rückstand durch Chromatographie an feinem Kieselgel. Isoliert werden 2,82 g (4,39 mmol, 63%) der Titelverbindung als farbloser Feststoff.
1H-NMR (CDCl3): 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 (1H), 2,29-2,97 (8H), 2,84 (3H), 3,14 (1H), 3,96 (1H), 4,03 (1H), 4,97-5,06 (2H), 5,23 (1H), 5,61 (1H), 5,77 (1H), 7,35 (1H), 7,79 (1H), 7,93 (1H) ppm.The solution of 5.3 g (7.01 mmol) (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-en-2,6-dione, which has been prepared in analogy to the process described in WO 00/66589, in one 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 are added dropwise and the mixture is stirred at 0 ° C. for 20 hours. 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 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 are isolated as a colorless solid.
1 H NMR (CDCl 3 ): 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 (1H), 2.29-2.97 (8H), 2.84 (3H), 3.14 (1H), 3.96 (1H), 4.03 (1H), 4.97-5.06 (2H), 5.23 (1H), 5.61 (1H), 5.77 (1H), 7.35 (1H), 7.79 (1H), 7.93 (1H) ppm.

Beispiel EL7bExample EL7b

(4S,7R,8S,9S,13Z,16S)-[3-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-propyl]-carbaminsäure-7-allyl-4-terf-butyl-dimethylsilyloxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-l3-en-8-yl ester(4S, 7R, 8S, 9S, 13Z, 16S) - [3- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -propyl] -carbamic acid-7-allyl-4-terf- butyl-dimethylsilyloxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexadec-I3-en-8-yl ester

100 mg (156 μmol) der nach Beispiel EL7a dargestellten Verbindung setzt man in Analogie zu Beispiel EL1 b mit dem nach Beispiel L4a hergestellten Linker um und isoliert nach Reinigung 121 mg (147 μmol, 94%) der Titelverbindung als farbloses Öl.100 mg (156 μmol) of that according to Example EL7a shown connection is set in analogy to example EL1 b around with the linker prepared according to Example L4a and isolated after Cleaning 121 mg (147 μmol, 94%) of the title compound as a colorless oil.

Beispiel EL7Example EL7

(4S,7R,8S,9S,13Z,16S)-[3-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-propyl]-carbaminsäure-7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yl ester(4S, 7R, 8S, 9S, 13Z, 16S) - [3- (2,5-dioxo-2,5-dihydro-pyrrol-1-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) der nach Beispiel EL7b dargestellten Verbindung setzt man in Analogie zu Beispiel EL1 um und isoliert nach Reinigung 17 mg (24 μmol, 43%) der Titelverbindung als farblosen Schaum.
1N-NMR (CDCl3): 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 (1H), 3,09 (1H), 3,14 (2H), 3,51 (1H), 3,58 (2H), 4,04 (1H), 4,96-5,04 (2H), 5,12 (1H), 5,19 (1H), 5,28 (1H), 5,75 (1H), 5,86 (1H), 6,66 (2H), 7,35 (1H), 7,78 (1H), 7,96 (1H) ppm.46 mg (56 μmol) of the compound shown in Example EL7b is reacted analogously to Example EL1 and, after purification, 17 mg (24 μmol, 43%) of the title compound is isolated as a colorless foam.
1 N NMR (CDCl 3 ): 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 (1H), 3.09 (1H), 3.14 (2H), 3.51 (1H), 3.58 (2H), 4.04 (1H), 4.96-5.04 (2H), 5.12 (1H), 5.19 (1H), 5.28 ( 1H), 5.75 (1H), 5.86 (1H), 6.66 (2H), 7.35 (1H), 7.78 (1H), 7.96 (1H) ppm.

Beispiel EL8Example EL8

(1S,3S,7S,10R,11S,12S,16R)-[3-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-propyl]-carbaminsäure-10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methylbenzothiazol-5-yl)-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-11-yl ester (A) und(1S, 3S, 7S, 10R, 11S, 12S, 16R) - [3- (2,5-dioxo-2,5-dihydro-pyrrol-1-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-11-yl ester (A) and

(1S,3S,7S,10R,11S,12S,16R)-[3-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-propyl]carbaminsäure-10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methylbenzothiazol-5-yl)-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-11-yl ester (B)(1S, 3S, 7S, 10R, 11S, 12S, 16R) - [3- (2,5-dioxo-2,5-dihydro-pyrrol-1-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-11-yl ester (B)

29 mg (41 μmol) der nach Beispiel EL7 dargestellten Verbindung setzt man in Analogie zu Beispiel EL2 um und isoliert nach Reinigung 18 mg (24,9 μmol, 61 %) der Titelverbindung A sowie 3,0 mg (4,1 μmol, 10%) der Titelverbindung B jeweils als farblosen Schaum.
1H-NMR (CDCl3) von 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 (1H), 2,84 (3H), 3,14 (2H), 3,59 (3H), 3,98 (1H), 4,10 (1H), 4,95-5,02 (2H), 5,17 (2H), 5,77 (1H), 6,19 (1H), 6,70 (2H), 7,38 (1H), 7,82 (1H), 7,97 (1H) ppm.
1H-NMR (CDCl3) von B: δ = 0,96 (3H), 1,01 (3H), 1,13-1,86 (11H), 1,28 (3H), 1,32 (1H), 2,16-2,50 (6H), 2,84 (3H), 3,02 (1H), 3,15 (2H), 3,50 (1H), 3,61 (2H), 3,88 (1H), 4,19 (1H), 4,96-5,04 (2H), 5,13 (1H), 5,28 (1H), 5,78 (1H), 6,33 (1H), 6,71 (2H), 7,36 (1H), 7,81 (1H), 7,96 (1H) ppm.29 mg (41 μmol) of the compound shown in Example EL7 is reacted analogously to Example EL2 and, after purification, 18 mg (24.9 μmol, 61%) of the title compound A and 3.0 mg (4.1 μmol, 10 %) of the title compound B in each case as a colorless foam.
1 H NMR (CDCl 3 ) 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 (1H), 2.84 (3H), 3.14 (2H), 3.59 (3H), 3, 98 (1H), 4.10 (1H), 4.95-5.02 (2H), 5.17 (2H), 5.77 (1H), 6.19 (1H), 6.70 (2H) , 7.38 (1H), 7.82 (1H), 7.97 (1H) ppm.
1 H NMR (CDCl 3 ) of B: δ = 0.96 (3H), 1.01 (3H), 1.13-1.86 (11H), 1.28 (3H), 1.32 (1H ), 2.16-2.50 (6H), 2.84 (3H), 3.02 (1H), 3.15 (2H), 3.50 (1H), 3.61 (2H), 3, 88 (1H), 4.19 (1H), 4.96-5.04 (2H), 5.13 (1H), 5.28 (1H), 5.78 (1H), 6.33 (1H) , 6.71 (2H), 7.36 (1H), 7.81 (1H), 7.96 (1H) ppm.

Beispiel EL9Example EL9

(4S,7R,8S,9S,13Z,16S)-[5-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-pentyl]-carbaminsäure-7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yl ester(4S, 7R, 8S, 9S, 13Z, 16S) - [5- (2,5-dioxo-2,5-dihydro-pyrrol-1-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

Beispiel EL9aExample EL9a

(4S,7R,8S,9S,13Z,16S)-[5-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-pentyl]-carbaminsäure-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(4S, 7R, 8S, 9S, 13Z, 16S) - [5- (2,5-dioxo-2,5-dihydro-pyrrol-1-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) der nach Beispiel EL7a dargestellten Verbindung setzt man in Analogie zu Beispiel EL1 b mit dem nach Beispiel L5a hergestellten Linker um und isoliert nach Reinigung 56 mg (65,9 μmol, 42%) der Titelverbindung als farbloses Öl.100 mg (156 μmol) of that according to Example EL7a shown connection is set in analogy to example EL1 b around with the linker prepared according to example L5a and isolated after Purification 56 mg (65.9 μmol, 42%) of the title compound as a colorless oil.

Beispiel EL9Example EL9

(4S,7R,8S,9S,13Z,16S)-[5-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-pentyl]-carbaminsäure-7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yl ester(4S, 7R, 8S, 9S, 13Z, 16S) - [5- (2,5-dioxo-2,5-dihydro-pyrrol-1-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) der nach Beispiel EL7b dargestellten Verbindung setzt man in Analogie zu Beispiel EL1 um und isoliert nach Reinigung 24,7 mg (33,6 μmol, 51 %) der Titelverbindung als farblosen Schaum.
1H-NMR (CDCl3): δ = 0,97-1,84 (11H), 1,02 (3H), 1,07 (3H), 1,20 (3H), 1,71 (3H), 1,91 (1H), 2,27-2,57 (6H), 2,84 (3H), 2,88 (1H), 2,95 (1H), 3,16 (2H), 3,51 (3H), 4,02 (1H), 4,46 + 4,83 (1H), 4,94-5,03 (2H), 5,15 (1H), 5,20 (1H), 5,74 (1H), 5,84 (1H), 6,68 (2H), 7,35 (1H), 7,80 (1H), 7,96 (1H) ppm.56 mg (65.9 μmol) of the compound shown in Example EL7b is reacted analogously to Example EL1 and, after purification, 24.7 mg (33.6 μmol, 51%) of the title compound is isolated as a colorless foam.
1 H-NMR (CDCl 3 ): δ = 0.97-1.84 (11H), 1.02 (3H), 1.07 (3H), 1.20 (3H), 1.71 (3H), 1.91 (1H), 2.27-2.57 (6H), 2.84 (3H), 2.88 (1H), 2.95 (1H), 3.16 (2H), 3.51 ( 3H), 4.02 (1H), 4.46 + 4.83 (1H), 4.94-5.03 (2H), 5.15 (1H), 5.20 (1H), 5.74 ( 1H), 5.84 (1H), 6.68 (2H), 7.35 (1H), 7.80 (1H), 7.96 (1H) ppm.

Beispiel EL10Example EL10

(1S,3S,7S,10R,11 S,12S,16R)-[5-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-pentyl]-carbaminsäure-10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methylbenzothiazol-5-yl)-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-11-yl ester (A) und(1S, 3S, 7S, 10R, 11 S, 12S, 16R) - [5- (2,5-Dioxo-2,5-dihydro-pyrrol-1-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-11-yl ester (A) and

(1S,3S,7S,10R,11S,12S,16R)-[5-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-pentyl]carbaminsäure-10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methylbenzothiazol-5-yl)-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-11-yl ester (B)(1S, 3S, 7S, 10R, 11S, 12S, 16R) - [5- (2,5-dioxo-2,5-dihydro-pyrrol-1-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-11-yl ester (B)

24,7 mg (33,6 μmol) der nach Beispiel EL9 dargestellten Verbindung setzt man in Analogie zu Beispiel EL2 um und isoliert nach Reinigung 16,7 mg (22,2 μmol, 66%) der Titelverbindung A sowie 2,0 mg (2,7 μmol, 8%) der Titelverbindung B jeweils als farblosen Schaum.
1H-NMR (CDCl3) von 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 (1H), 2,84 (3H), 3,15 (2H), 3,51 (2H), 3,57 (1H), 3,99 (1H), 4,08 (1H), 4,46+4,74 (1H), 4,93-5,02 (2H), 5,18 (1H), 5,76 (1H), 6,18 (1H), 6,68 (2H), 7,38 (1H), 7,82 (1H), 7,97 (1H) ppm.
1H-NMR (CDCl3) von 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 (1H), 3,17 (2H), 3,48 (1H), 3,53 (2H), 3,86 (1H), 4,18 (1H), 4,66 (1H), 4,94-5,03 (2H), 5,27 (1H), 5,76 (1H), 6,33 (1H), 6,69 (2H), 7,35 (1H), 7,81 (1H), 7,96 (1H) ppm.24.7 mg (33.6 μmol) of the compound shown in Example EL9 is reacted analogously to Example EL2 and, after purification, 16.7 mg (22.2 μmol, 66%) of the title compound A and 2.0 mg ( 2.7 μmol, 8%) of the title compound B in each case as a colorless foam.
1 H NMR (CDCl 3 ) 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 (1H), 2.84 (3H), 3.15 (2H), 3.51 (2H), 3.57 (1H), 3, 99 (1H), 4.08 (1H), 4.46 + 4.74 (1H), 4.93-5.02 (2H), 5.18 (1H), 5.76 (1H), 6, 18 (1H), 6.68 (2H), 7.38 (1H), 7.82 (1H), 7.97 (1H) ppm.
1 H NMR (CDCl 3 ) 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 (1H), 3.17 (2H), 3.48 (1H), 3.53 (2H), 3, 86 (1H), 4.18 (1H), 4.66 (1H), 4.94-5.03 (2H), 5.27 (1H), 5.76 (1H), 6.33 (1H) , 6.69 (2H), 7.35 (1H), 7.81 (1H), 7.96 (1H) ppm.

Beispiel EL11Example EL11

(1 S,3S(E),7S,10R,11S,12S,16R)-[3-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-propyl]-carbaminsäure 7-[3-(2,5-dioxo-2,5-dihydro-pyrrol-1-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-11-yl ester(1 S, 3S (E), 7S, 10R, 11S, 12S, 16R) - [3- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) propyl] carbamic acid 7- [ 3- (2,5-dioxo-2,5-dihydro-pyrrol-1-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-11-yl ester

10 mg (19,7 μmol) (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-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]heptadecan setzt man in Analogie zu Beispiel EL1b mit dem nach Beispiel L4a hergestellten Linker um und isoliert nach Reinigung 7 mg (8,06 μmol, 41 %) der Titelverbindung als farbloses Öl.
1H-NMR (CDCl3): 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 (1 H), 6,69 (2H), 6,71 (2H), 7,02 (1 H) ppm.10 mg (19.7 μmol) (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-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] heptadecane is used in analogy to example EL1b with that according to example L4a Linker prepared and isolated after purification 7 mg (8.06 μmol, 41%) of the title compound as a colorless oil.
1 H-NMR (CDCl 3 ): 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 (1H), 6.69 (2H), 6.71 (2H), 7.02 (1H ) ppm.

Analog zu den genannten Beispielen werden folgende Effektorkonjugate erhalten:Analogous to the examples mentioned the following effector conjugates are obtained:

Beispiel EL12Example EL12

(4S,7R,8S,9S,13Z,16S)-Kohlensäure 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(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

(Als Zwischenprodukt wird (4S,7R,8S,9S,13Z,16S)-Kohlensäure 7-allyl-8-(tertbutyl-dimethyl-silanyloxy)-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 isoliert.)(As an intermediate (4S, 7R, 8S, 9S, 13Z, 16S) -carbonic acid 7-allyl-8- (tertbutyl-dimethyl-silanyloxy) -5,5,9,13-tetramethyl-16- (2-methyl- benzothiazol-5-yl) -2,6-dioxo-oxacyclohexadec-13-en-4-yl 4- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) phenyl ester isolated.)

Beispiel EL13Example EL13

(1 S,3S,7S,10R,11S,12S,16R)-Kohlensäure-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-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-phenyl ester(1 S, 3S, 7S, 10R, 11S, 12S, 16R) -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- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) phenyl ester

Beispiel EL14Example EL14

(4S,7R,8S,9S,13Z,16S)-Kohlensäure 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(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

(Als Zwischenprodukt wird (4S,7R,8S,9S,13Z,16S)-Kohlensäure 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-1-yl)-phenyl ester isoliert.)(As an intermediate (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 4- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) phenyl ester isolated.)

Beispiel EL15Example EL15

(1S,3S,7S,10R,11S,12S,16R)-Kohlensäure-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-yl ester 4-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-phenyl ester(1S, 3S, 7S, 10R, 11S, 12S, 16R) -Carbonic-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-yl ester 4- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) phenyl ester

Beispiele zur Synthese von Effektor-Linker-Erkennungseinheiten (ELE)Examples for the synthesis of Effector linker recognition units (ELE)

Beispiel ELE1Example ELE1

[3-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-propyl]-carbaminsäure-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[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

Beispiel ELE1aExample ELE1a

Reduktion eines Antikörperfragments mit endständigem CysteinReduction of one Antibody fragment with terminal cysteine

Ein einzelsträngiges Protein bestehend aus den variablen Domänen der schweren und leichten Antikörper Kette (single-chain Fv, scFv) der Aminosäurenabfolge EVQLLESGGGLVQPGGSLRLSCAASGFTFSSFSMSWV RQAPGKGLEVWSSISGSSGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAED TAVyyCAKPFPYFDYWGQGTLVTVSSGDGSSGGSGGASEIVLTQSPGTLSLSP GERATLSCRASQSVSSSFLAWYQQKPGQAPRLLIYYASSRATGIPDRFSGSGS GTDFTLTISRLEPEDFAVYYCQQTGRIPPTFGQGTKVEIKGGGCA, das spezifisch die Fibronektin Domäne B (ED-B) erkennt und als AP39 bezeichnet wird, wird nach Reduktion des c-terminalen Cysteins zur Kopplung verwendet. Zur Reduktion wird die Lösung von 661 μg Tri(2-carboxyethyl)phosphin-Hydrochlorid in 236 μl PBS mit der Lösung von 1,54 mg AP39 in 1,12 ml PBS versetzt und für 1,5 Stunden bei 25°C inkubiert. Man entsalzt mit einer voräquilibrierten NAP5-Säule bei einer Beladung mit 450 μl AP39r und 50 μl PBS. Nach Elution mit 1 ml PBS isoliert man das reduzierte Antikörperfragment AP39r in einer Konzentration von 0,7 mg/ml.A single-stranded protein consisting of the variable domains the heavy and light antibodies Chain (single-chain Fv, scFv) of the amino acid sequence EVQLLESGGGLVQPGGSLRLSCAASGFTFSSFSMSWV RQAPGKGLEVWSSISGSSGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAED TAVyyCAKPFPYFDYWGQGTLVTVSSGDGSSGGSGGASEIVLTQSPGTLSLSP GERATLSCRASQSVSSKGSSGR GTDFTLTISRLEPEDFAVYYCQQTGRIPPTFGQGTKVEIKGGGCA, which specifically the Fibronectin domain B (ED-B) recognizes and is referred to as AP39, after reduction of the c-terminal cysteine used for coupling. For reduction the solution of 661 μg Tri (2-carboxyethyl) phosphine hydrochloride in 236 μl PBS with the solution of 1.54 mg AP39 in 1.12 ml PBS and incubated for 1.5 hours at 25 ° C. Desalinate with a pre-equilibrated NAP5 column with a load of 450 μl AP39r and 50 μl PBS. After elution with 1 ml PBS, the reduced antibody fragment is isolated AP39r in a concentration of 0.7 mg / ml.

Beispiel ELE1Example ELE1

(1S,3S,7S(3RS),10R,11S,12S,16R)-[3-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-propyl]-carbaminsäure-10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methylbenzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo(14.1.0]heptadec-7-yl ester(1S, 3S, 7S (3RS), 10R, 11S, 12S, 16R) - [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

Zu 400 μl der nach Beispiel ELE1 a dargestellten Lösung des reduzierten Antikörperfragmentes gibt man 22,5 μl einer 1,38 mM Lösung des nach Beispiel EL2 dargestellten Effektor-Linker-Konjugates A in DMSO, versetzt mit 77,5 μl PBS und inkubiert bei 25°C für 1 Stunde. Man entsalzt mit einer voräquilibrierten NAP5-Säule bei einer Beladung mit 500 μl der Reaktionslösung. Nach Elution mit PBS isoliert man die Lösung der Titelverbindung. Der Verdünnungsfaktor bezogen auf das Antikörperfragment beträgt ca. 2,5.To 400 μl of that shown in Example ELE1 a solution of the reduced antibody fragment give 22.5 ul a 1.38 mM solution of the effector-linker conjugate A shown in Example EL2 in DMSO, mixed with 77.5 μl PBS and incubated at 25 ° C for 1 hour. Desalt with a pre-equilibrated NAP5 column a load of 500 μl the reaction solution. After elution with PBS, the solution of the title compound is isolated. The dilution factor based on the antibody fragment is about 2.5.

Beispiel ELE2Example ELE2

(1S,3S,7S(3RS),10R,11S,12S,16R)-[5-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-pentyl]-carbaminsäure-10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methylbenzothiazol-5-yl)-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-7-yl ester(1S, 3S, 7S (3RS), 10R, 11S, 12S, 16R) - [5- (3- (AP39r) -sulfanyl-2,5-dioxo-pyrrolidin-1-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

In Analogie zu Beispiel ELE1 setzt man das nach Beispiel ELE1a reduzierte Antikörperfragment mit dem nach Beispiel EL4 dargestellten Effektor-Linker-Konjugat A um und isoliert die Lösung der Titelverbindung. Der Verdünnungsfaktor bezogen auf das Antikörperfragment beträgt ca. 2,5.In analogy to example ELE1 sets the antibody fragment reduced according to example ELE1a with that according to example EL4 shown effector-linker conjugate A and isolates the solution of the Title compound. The dilution factor based on the antibody fragment is about 2.5.

Beispiel ELE3Example ELE3

(1S,3S,7S(3RS),10R,11S,12S,16R)-[10-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-decyl]-carbaminsäure-10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methylbenzothiazol-5-yl)-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-7-yl ester(1S, 3S, 7S (3RS), 10R, 11S, 12S, 16R) - [10- (3- (AP39r) -sulfanyl-2,5-dioxo-pyrrolidin-1-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

In Analogie zu Beispiel ELE1 setzt man das nach Beispiel ELE1a reduzierte Antikörperfragment mit dem nach Beispiel EL6 dargestellten Effektor-Linker-Konjugat A um und isoliert die Lösung der Titelverbindung. Der Verdünnungsfaktor bezogen auf das Antikörperfragment beträgt ca. 2,5.In analogy to example ELE1 sets the antibody fragment reduced according to example ELE1a with that according to example EL6 shown effector-linker conjugate A and isolated the solution of Title compound. The dilution factor based on the antibody fragment is about 2.5.

Beispiel ELE4Example ELE4

(1S,3S,7S,10R,11S(3RS),12S,16R)-[3-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-propyl]-carbaminsäure-10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methylbenzothiazol-5-yl)-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-11-yl ester(1S, 3S, 7S, 10R, 11S (3RS), 12S, 16R) - [3- (3- (AP39r) -sulfanyl-2,5-dioxo-pyrrolidin-1-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-11-yl ester

In Analogie zu Beispiel ELE1 setzt das nach Beispiel ELE1a reduzierte Antikörperfragment mit dem nach Beispiel EL8 dargestellten Effektor-Linker-Konjugat A um und isoliert die Lösung der Titelverbindung. Der Verdünnungsfaktor bezogen auf das Antikörperfragment beträgt ca. 2,5.In analogy to example ELE1 sets the antibody fragment reduced according to example ELE1a with that according to example EL8 shown effector-linker conjugate A and isolated the solution of Title compound. The dilution factor based on the antibody fragment is about 2.5.

Beispiel ELE5Example ELE5

(1S,3S,7S,10R,11S(3RS),12S,16R)-[5-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-pentyl]-carbaminsäure-10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methylbenzothiazol-5-yl)-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-11-yl ester(1S, 3S, 7S, 10R, 11S (3RS), 12S, 16R) - [5- (3- (AP39r) -sulfanyl-2,5-dioxo-pyrrolidin-1-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-11-yl ester

In Analogie zu Beispiel ELE1 setzt das nach Beispiel ELE1a reduzierte Antikörperfragment mit dem nach Beispiel EL10 dargestellten Effektor-Linker-Konjugat A um und isoliert die Lösung der Titelverbindung. Der Verdünnungsfaktor bezogen auf das Antikörperfragment beträgt ca. 2,5.In analogy to example ELE1 sets the antibody fragment reduced according to example ELE1a with that according to example EL10 shown effector-linker conjugate A and isolated the solution of Title compound. The dilution factor based on the antibody fragment is about 2.5.

Beispiel ELE6Example ELE6

(1S,3S(E),7S,10R,11 S,12S,16R)-[3-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-propyl]-carbaminsäure-7-[3-(2,5-dioxo-2,5-dihydro-pyrrol-1-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-1l-yl ester (A) und(1S, 3S (E), 7S, 10R, 11 S, 12S, 16R) - [3- (3- (AP39r) -sulfanyl-2,5-dioxopyrrolidin-1-yl) propyl] carbamic acid - 7- [3- (2,5-dioxo-2,5-dihydr o-pyrrol-1-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-1l-yl ester (A) and

(1S,3S(E),7S,10R,11S,12S,16R)-[3-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-propyl]-carbaminsäure-11-[3-(2,5-dioxo-2,5-dihydro-pyrrol-1-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)(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) - [3- (3- (AP39r) -sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -propyl] -carbamic acid-11 - [3- (2,5-dioxo-2,5-dihydro-pyrrol-1-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)

In Analogie zu Beispiel ELE1 setzt das nach Beispiel ELE1a reduzierte Antikörperfragment mit dem nach Beispiel EL11 dargestellten Effektor-Linker-Konjugat um und isoliert die Lösung der Titelverbindungen. Der Verdünnungsfaktor bezogen auf das Antikörperfragment beträgt ca. 2,5.In analogy to example ELE1 sets the antibody fragment reduced according to example ELE1a with that according to example EL11 shown effector-linker conjugate and isolated the solution of Title compounds. The dilution factor based on the antibody fragment is about 2.5.

Claims (19)

Effektor-Konjugat der allgemeinen Formel (I):
Figure 00580001
worin R1a, R1b unabhängig voneinander Wasserstoff, C1-C10 Alkyl, Aryl, Aralkyl, oder gemeinsam eine -(CH2)m-Gruppe sind, worin m 2 bis 5 ist, R2a, R2b unabhängig voneinander Wasserstoff, C1-C10 Alkyl, Aryl, Aralkyl, oder gemeinsam eine -(CH2)n-Gruppe sind, worin n 2 bis 5 ist, oder C2-C10 Alkenyl, oder C2-C10 Alkinyl, R3 Wasserstoff, C1-C10Alkyl, Aryl oder Aralkyl, und R4a, R4b unabhängig voneinander Wasserstoff, C1-C10 Alkyl, Aryl, Aralkyl, oder gemeinsam eine -(CH2)p-Gruppe sind, worin p 2 bis 5 ist, R5 Wasserstoff, C1-C10 Alkyl, Aryl, Aralkyl, CO2H, CO2Alkyl, CH2OH, CH2OAlkyl, CH2OAcyl, CN, CH2NH2, CH2N(Alkyl, Acyl)1,2, oder CH2Hal, Hal ein Halogen-Atom, R6, R7 jeweils Wasserstoff, oder gemeinsam eine zusätzliche Bindung, oder gemeinsam ein Sauerstoff-Atom, oder gemeinsam eine NH-Gruppe, oder gemeinsam eine N-Alkyl-Gruppe, oder gemeinsam eine CH2-Gruppe, und G ein Sauerstoffatom oder CH2 sind, D–E eine Gruppe H2C-CH2, HC=CH, C≡C, CH(OH)-CH(OH), CH(OH)-CH2, CH2 CH((OH), HC O / -CH, O-CH2, O-CH2 oder, falls G eine CH2-Gruppe darstellt, CH2-O ist, W eine Gruppe C(=X)R8, oder ein bi- oder tricyclischer aromatischer oder heteroaromatischer Rest ist, L3 Wasserstoff ist, oder, falls ein Rest in W eine Hydroxyl-Gruppe enthält, mit dieser eine Gruppe O-L4 bildet, oder, falls ein Rest in W eine Amino-Gruppe enthält, mit dieser eine Gruppe NR25-L4 bildet, R25 Wasserstoff oder C1-C10 Alkyl ist, X ein Sauerstoffatom, oder zwei OR20-Gruppen, oder eine C2-C10 Alkylendioxy-Gruppe, die geradkettig oder verzweigt sein darf, oder H/OR9, oder eine CR10R11-Gruppe, R8 Wasserstoff, C1-C10 Alkyl, Aryl, Aralkyl, Halogen oder CN, und R9 Wasserstoff oder eine Schutzgruppe PGX sind, R10, R11 jeweils unabhängig voneinander Wasserstoff, C1-C20 Alkyl, Aryl, Aralkyl sind, oder gemeinsam mit einem Methylenkohlenstoffatom einen 5- bis 7-gliedrigen carbocyclischen Ring bilden, Z Sauerstoff oder H/OR12, R12 Wasserstoff oder eine Schutzgruppe PGZ, A-Y eine Gruppe O-C(=O), O-CH2, CH2-C(=O), NR21-C(=O) oder NR21-SO2, R20 C1-C20 Alkyl, R21 ein Wasserstoffatom oder C1-C20 Alkyl, PGX, PGY, PGZ eine Schutzgruppe PG, und L1, L2, L4 unabhängig voneinander Wasserstoff, eine Gruppe C(=O)Cl, eine Gruppe C(=S)Cl, eine Gruppe PGY oder einen Linker der allgemeinen Formel (III) darstellen können; mit der Bedingung, dass mindestens ein Substituent L1, L2 oder L4 einen Linker der allgemeinen Formel (III) darstellt; der Linker der allgemeinen Formel (III) folgende Struktur hat,
Figure 00610001
worin T Sauerstoff oder Schwefel, U Sauerstoff, CHR22, CHR22-NR23-C(=O)-, O-C(=O)-CHR22-NR23-C(=O)-, O-C(=O)-CHR22-NR23-C(=S)-, CHR22-NR23-C(=S)- oder NR24a, o 0 bis 15, V eine Bindung, Aryl, eine Gruppe
Figure 00610002
oder eine Gruppe
Figure 00610003
s 0 bis 4, Q eine Bindung, O-C(=O)-NR24c, O-C(=S)-NR24c,
Figure 00610004
R22 Wasserstoff, C1-C10 Alkyl, Aryl oder Aralkyl R23 Wasserstoff oder C1-C10 Alkyl, R24a, R24b, R24c unabhängig voneinander Wasserstoff oder C1-C10 Alkyl, q 0 bis 15, FG1 C1-C10Alkyl-S3- oder
Figure 00620001
darstellen können; als einheitliches Isomer oder eine Mischung unterschiedlicher Isomere und/oder als ein pharmazeutisch akzeptables Salz hiervon.Effector conjugate of the general formula (I):
Figure 00580001
wherein R 1a , R 1b independently of one another are hydrogen, C 1 -C 10 alkyl, aryl, aralkyl, or together are a - (CH 2 ) m group, wherein m is 2 to 5, R 2a , R 2b independently of one another are hydrogen, C 1 -C 10 alkyl, aryl, aralkyl, or together are a - (CH 2 ) n group, in which n is 2 to 5, or C 2 -C 10 alkenyl, or C 2 -C 10 alkynyl, R 3 is hydrogen , C 1 -C 10 alkyl, aryl or aralkyl, and R 4a , R 4b independently of one another are hydrogen, C 1 -C 10 alkyl, aryl, aralkyl, or together are a - (CH 2 ) p group, in which p 2 to 5 is, R5 is hydrogen, C 1 -C 10 alkyl, aryl, aralkyl, CO 2 H, CO 2 alkyl, CH 2 OH, CH 2 O alkyl, CH 2 O acyl, CN, CH 2 NH 2 , CH 2 N (alkyl, Acyl) 1,2 , or CH 2 Hal, Hal is a halogen atom, R 6 , R 7 are each 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 CH 2 group, and G is an oxygen atom or CH 2 , D-E is a group e H 2 C-CH 2 , HC = CH, C≡C, CH (OH) -CH (OH), CH (OH) -CH 2 , CH 2 CH ((OH), HC O / -CH, O- CH 2 , O-CH 2 or, if G represents a CH 2 group, is CH 2 -O, W is a group C (= X) R 8 , or a bi- or tricyclic aromatic or heteroaromatic radical, L 3 is hydrogen or, if a radical in W contains a hydroxyl group, forms an OL 4 group with it, or, if a radical in W contains an amino group, forms a group NR 25 -L 4 with it, R 25 forms hydrogen or C 1 -C 10 alkyl, X is an oxygen atom, or two OR 20 groups, or a C 2 -C 10 alkylenedioxy group, which may be straight-chain or branched, or H / OR 9 , or a CR 10 R 11 -Group, R8 are hydrogen, C 1 -C 10 alkyl, aryl, aralkyl, halogen or CN, and R 9 are hydrogen or a protective group PG X , R 10 , R 11 are each independently hydrogen, C 1 -C 20 alkyl, aryl , Aralkyl, or together with a methylene carbon atom a 5- to 7-membered carbocyclic ring bil den, Z oxygen or H / OR 12 , R 12 hydrogen or a protective group PG Z , AY is a group OC (= O), O-CH 2 , CH2-C (= O), NR 21 -C (= O) or NR 21 -SO 2 , R 20 C 1 -C 20 alkyl, R 21 is a hydrogen atom or C 1 -C 20 alkyl, PG X , PG Y , PG Z a protective group PG, and L 1 , L 2 , L 4 independently of one another hydrogen, a group C (= O) Cl, a group C (= S) Cl , can represent a group PG Y or a linker of the general formula (III); with the condition that at least one substituent L 1 , L 2 or L 4 represents a linker of the general formula (III); the linker of the general formula (III) has the following structure,
Figure 00610001
where T is oxygen or sulfur, U is oxygen, CHR 22 , CHR 22 -NR 23 -C (= O) -, OC (= O) -CHR 22 -NR 23 -C (= O) -, OC (= O) - CHR 22 -NR 23 -C (= S) -, CHR 22 -NR 23 -C (= S) - or NR 24a , o 0 to 15, V a bond, aryl, a group
Figure 00610002
or a group
Figure 00610003
s 0 to 4, Q is a bond, OC (= O) -NR 24c , OC (= S) -NR 24c ,
Figure 00610004
R 22 hydrogen, C 1 -C 10 alkyl, aryl or aralkyl R 23 hydrogen or C 1 -C 10 alkyl, R 24a , R 24b , R 24c independently of one another hydrogen or C 1 -C 10 alkyl, q 0 to 15, FG 1 C 1 -C 10 alkyl S 3 - or
Figure 00620001
can represent; as a uniform isomer or a mixture of different isomers and / or as a pharmaceutically acceptable salt thereof. Effektor-Konjugat gemäß Anspruch 1, wobei: A-Y O-C(=O) oder NR21-C(=O), D-E eine H2C-CH2-Gruppe, G eine CH2-Gruppe, Z ein Sauerstoffatom, R1a, R1b jeweils C1-C10 Alkyl oder zusammen eine -(CH2)p-Gruppe mit p gleich 2 oder 3 oder 4, R2a, R2b unabhängig voneinander Wasserstoff, C1-C10 Alkyl, C2-C10 Alkenyl, oder C2-C10 Alkinyl, R3 Wasserstoff; R4a, R4b unabhängig voneinander Wasserstoff oder C1-C10 Alkyl; R5 Wasserstoff, oder C1-C4 Alkyl oder CH2OH oder CH2NH2 oder CH2N(Alkyl, Acyl)1,2 oder CH2Hal, R6 und R7 gemeinsam eine zusätzliche Bindung oder gemeinsam eine NH-Gruppe oder gemeinsam eine N-Alkyl-Gruppe oder gemeinsam eine CH2-Gruppe, oder gemeinsam ein Sauerstoffatom, W eine Gruppe C(=X)R8 oder ein 2-Methylbenzothiazol-5-yl-Radikal oder ein 2-Methylbenzoxazol-5-yl-Radikal oder ein Chinolin-7-yl-Radikal oder ein 2-Aminomethylbenzothiazol-5-yl-Radikal oder ein 2-Hydroxymethylbenzothiazol-5-yl-Radikal oder ein 2-Aminomethyl-benzoxazol-5-yl-Radikal oder ein 2-Hydroxymethylbenzoxazol-5-yl-Radikal, X eine CR10R11-Gruppe R8 Wasserstoff oder C1-C4 Alkyl oder ein Fluoratom oder ein Chloratom oder ein Bromatom, R10/R11 Wasserstoff/2-Methylthiazol-4-yl oder Wasserstoff/2-Pyridyl oder Wasserstoff/2-Methyloxazol-4-yl oder Wasserstoff/2-Aminomethylthiazol-4-yl oder Wasserstoff/2-Aminomethyloxazol-4-yl oder Wasserstoff/2-Hydroxymethylthiazol-4-yl oder Wasserstoff/2-Hydroxymethyloxazol-4-yl darstellen.Effector conjugate according to claim 1, wherein: AY OC (= O) or NR 21 -C (= O), DE is an H 2 C-CH 2 group, G is a CH2 group, Z is an oxygen atom, R 1a , R 1b each C 1 -C 10 alkyl or together a - (CH 2 ) p group with p equal to 2 or 3 or 4, R 2a , R 2b independently of one another hydrogen, C 1 -C 10 Alkyl, C 2 -C 10 alkenyl, or C 2 -C 10 alkynyl, R 3 hydrogen; R 4a , R 4b independently of one another are hydrogen or C 1 -C 10 alkyl; R 5 is hydrogen, or C 1 -C 4 alkyl or CH 2 OH or CH 2 NH 2 or CH 2 N (alkyl, acyl) 1,2 or CH 2 Hal, R6 and R7 together form an additional bond or together form an NH group or together an N-alkyl group or together a CH2 group, or together an oxygen atom, W a group C (= X) R 8 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 a CR 10 R 11 group R 8 hydrogen or C 1 -C 4 alkyl or a fluorine atom or a chlorine atom or a bromine atom, R 10 / R 11 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 -hydro represent xymethyloxazol-4-yl. Effektor-Konjugat gemäß Anspruch 1 oder 2, wobei der Effektor-Grundkörper ausgewählt ist aus der Gruppe bestehend aus: (4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-(1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-en-2,6-dion; (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-en-2,6-dion; (4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-Aminomethyl-thiazol-4-yl)-1-methylvinyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-en-2,6-dion; (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethylthiazol-4-yl)-1-methyl-vinyl]-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S(E),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-1-methyl-vinyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4-yl)-1-methyl-vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-Aminomethyl-thiazol-4-yl)-1-methylvinyl]-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dion; (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3-[1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethylthiazol-4-yl)-1-methyl-vinyl]-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S(E),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-1-methyl-vinyl]-7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-fluor-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4-yl)-1-fluor-vinyl]-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-thiazol-4-yl)-1-fluorvinyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-en-2,6-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-fluor-2-(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethylthiazol-4-yl)-1-fluor-vinyl]-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-1-fluorvinyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-chlor-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4-yl)-1-chlor-vinyl]-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-thiazol-4-yl)-1-chlorvinyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-en-2,6-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-chlor-2-(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethylthiazol-4-yl)-1-chlor-vinyl]-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-1-chlorvinyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[1-fluor-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4-yl)-1-fluor-vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-thiazol-4-yl)-1-fluorvinyl]-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3-[1-fluor-2-(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethylthiazol-4-yl)-1-fluor-vinyl]-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-1-fluorvinyl]-7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[1-chlor-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4-yl)-1-chlor-vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-thiazol-4-yl)-1-chlorvinyl]-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8;12,16-tetramethyl-3-[1-chlor-2-(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethylthiazol-4-yl)-1-chlor-vinyl]-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-1-chlorvinyl]-7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-pyridyl)-vinyl]-oxacyclohexadec-13-en-2,6-dion; (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[1-methyl-2-(2-pyridyl)-vinyl]-oxacyclohexadec-l3-en-2,6-dion; (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3-[1-methyl-2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-fluor-2-(2-pyridyl)-vinyl]-oxacyclohexadec-13-en-2,6-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-fluor-2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-chlor-2-(2-pyridyl)-vinyl]-oxacyclohexadec-13-en-2,6-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-chlor-2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[1-fluor-2-(2-pyridyl)-vinyl]-oxacyclohexadec-13-en-2,6-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3-[1-fluor-2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-l6-[1-chlor-2-(2-pyridyl)-vinyl]-oxacyclohexadec-13-en-2,6-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3-(1-chlor-2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4-yl)-1-methyl-vinyl]-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-Aminomethyl-oxazol-4-yl)-1-methylvinyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-en-2,6-dion; (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]heptadecan-5,9-dion; (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyloxazol-4-yl)-1-methyl-vinyl]-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S(E),7S,10R,11 S,12S,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-1-methyl-vinyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[1-methyl-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4-yl)-1-methyl-vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-Aminomethyl-oxazol-4-yl)-1-methylvinyl]-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dion; (1S,3S(E),7S,10R,11S,12S,16R)-7,11-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]heptadecan-5,9-dion; (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-(2-hydroxymethyloxazol-4-yl)-1-methyl-vinyl]-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S(E),7S,10R,11S,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]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-fluor-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4-yl)-1-fluor-vinyl]-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-oxazol-4-yl)-1-fluorvinyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-en-2,6-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-fluor-2-(2-methyl-oxazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-(2-hydroxymethyloxazol-4-yl)-1-fluor-vinyl]-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-1-fluorvinyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-chlor-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4-yl)-1-chlor-vinyl]-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-oxazol-4-yl)-1-chlorvinyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-en-2,6-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-chlor-2-(2-methyl-oxazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyloxazol-4-yl)-1-chlor-vinyl]-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-1-chlorvinyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[1-fluor-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4-yl)-1-fluor-vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-oxazol-4-yl)-1-fluorvinyl]-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3-[1-fluor-2-(2-methyl-oxazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyloxazol-4-yl)-1-fluor-vinyl]-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-1-fluorvinyl]-7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[1-chlor-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4-yl)-1-chlor-vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-oxazol-4-yl)-1-chlorvinyl]-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3-[1-chlor-2-(2-methyl-oxazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyloxazol-4-yl)-1-chlor-vinyl]-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-1-chlorvinyl]-7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (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-en-2,6-dion; (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-en-2,6-dion; (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-en-2,6-dion; (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8;10,12,16-pentamethyl-3-[2-(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethylthiazol-4-yl)-vinyl]-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S(E),7S,10R,11S,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]heptadecan-5,9-dion; (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-l3-en-2,6-dion; (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-en-2,6-dion; (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-en-2,6-dion; (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3-[2-(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethylthiazol-4-yl)-vinyl]-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S(E),7S,10R,11S,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]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[2-(2-pyridyl)-vinyl]-oxacyclohexadec-13-en-2,6-dion; (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[2-(2-pyridyl)-vinyl]-oxacyclohexadec-13-en-2,6-dion; (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3-[2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-(2-methyl-benzothiazol-5-yl)-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5-yl)-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-en-2,6-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-(2-methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethylbenzothiazol-5-yl)-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5-yl)-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S, 3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethylbenzothiazol-5-yl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S,7S,10R,11S,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]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-propyl-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5-yl)-7-propyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy-7-propyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-propyl-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethylbenzothiazol-5-yl)-10-propyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S,7S,10R,11S,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]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-butyl-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5-yl)-7-butyl-5,5,9,13-tetramethyl-oxacyclohexadec-l3-en-2,6-dion; (4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy-7-butyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-butyl-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethylbenzothiazol-5-yl)-10-butyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,11-dihydroxy-10-butyl-8,8;12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-allyl-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5-yl)-7-allyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy-7-allyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-allyl-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethylbenzothiazol-5-yl)-10-allyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,11-dihydroxy-10-allyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (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-en-2,6-dion; (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-en-2,6-dion; (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-en-2,6-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-prop-2-inyl-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethylbenzothiazol-5-yl)-10-prop-2-inyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,11-dihydroxy-10-prop-2-inyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (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-en-2,6-dion; (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-en-2,6-dion; (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-en-2,6-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-but-3-enyl-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethylbenzothiazol-5-yl)-10-but-3-enyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S,7S,10R,11S,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]heptadecan-5,9-dion; (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-en-2,6-dion; (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-en-2,6-dion; (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-en-2,6-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-but-3-inyl-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethylbenzothiazol-5-yl)-10-but-3-inyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,11-dihydroxy-10-but-3-inyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-(2-methyl-benzoxazol-5-yl)-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5-yl)-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-en-2,6-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-(2-methyl-benzoxazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethylbenzoxazol-5-yl)-8, 8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-(2-methyl-benzoxazol-5-yl)-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5-yl)-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dion; (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]heptadecan-5,9-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethylbenzoxazol-5-yl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-propyl-5,5,9,13-tetramethyl-16-(2-methyl-benzoxazol-5-yl)-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5-yl)-7-propyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy-7-propyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-propyl-8,8,12,16-tetramethyl-3-(2-methyl-benzoxazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethylbenzoxazol-5-yl)-10-propyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,11-dihydroxy-10-propyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-butyl-5,5,9,13-tetramethyl-16-(2-methyl-benzoxazol-5-yl)-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5-yl)-7-butyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy-7-butyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-butyl-8,8,12,16-tetramethyl-3-(2-methyl-benzoxazol-5-yl)-4,17-dioxabicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethylbenzoxazol-5-yl)-10-butyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,11-dihydroxy-10-butyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-allyl-5,5,9,13-tetramethyl-16-(2-methyl-benzoxazol-5-yl)-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5-yl)-7-allyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dion; (4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy-7-allyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dion; (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]heptadecan-5,9-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethylbenzoxazol-5-yl)-10-allyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,11-dihydroxy-10-allyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (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-en-2,6-dion; (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-en-2,6-dion; (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-en-2,6-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-prop-2-inyl-8,8,12,16-tetramethyl-3-(2-methyl-benzoxazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethylbenzoxazol-5-yl)-10-prop-2-inyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S,7S,10R,11S,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]heptadecan-5,9-dion; (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-en-2,6-dion; (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-l3-en-2,6-dion; (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-en-2,6-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-but-3-enyl-8,8,12,16-tetramethyl-3-(2-methyl-benzoxazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethylbenzoxazol-5-yl)-10-but-3-enyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1 S,3S,7S,10R,11 S,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,11-dihydroxy-10-but-3-enyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo(14.1.0]heptadecan-5,9-dion; (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-en-2,6-dion; (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-en-2,6-dion; (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-en-2,6-dion; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-but-3-inyl-8,8,12,16-tetramethyl-3-(2-methyl-benzoxazol-5-yl)-4,17-dioxabicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S,7S,10R,11 ,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethylbenzoxazol-5-yl)-10-but-3-inyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion; (1S,3S,7S,10R,11 S,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,11-dihydroxy-10-but-3-inyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecan-5,9-dion, wobei an den in Formel (1) angegebenen Positionen die Wasserstoffatome in den vorstehend genannten Effektor-Grundkörpern durch Reste L1-L3 ersetzt sind.The effector conjugate according to claim 1 or 2, wherein the effector base is selected from the group consisting of: (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-5,5,7 , 9,13-pentamethyl-16- (1-methyl-2- (2-methylthiazol-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-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 16- [2- (2-aminomethylthiazol-4-yl) -1- methylvinyl] -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-thiazol-4-yl) -vinyl] -4.17-dioxa bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethylthiazole-4 -yl) -1-methyl-vinyl] -8,8,10,12,16-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (E) , 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-thiazol-4-yl) -1-methyl-vinyl] -7,11-dihydroxy-8,8,10,12, 16-pentamet hyl-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- [1-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] -7-ethyl -5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 16- [2- (2-Aminomethyl-thiazol-4-yl) -1-methyl vinyl] -4,8-dihydroxy-7-ethyl-5 , 5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-methyl-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) -7,11-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] heptadecane-5,9-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-thiazol-4-yl) -1-methyl-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 (Z)) - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-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-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 16- [2- (2-Aminomethyl-thiazol-4-yl) -1-fluorovinyl] -4,8-dihydroxy-5,5,7 , 9,13-pentamethyl-oxacyclohexadec-13-en-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; (1S, 3S (Z), 7S, 10R, 11S, 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; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-thiazol-4-yl) -1-fluorovinyl] -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- [1-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] -5,5 , 7,9,13- penta methyl-oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 16- [2- (2-Aminomethyl-thiazol-4-yl) -1-chloro vinyl] -4,8-dihydroxy-5,5,7 , 9,13-pentamethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-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) -7,11-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; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-thiazol-4-yl) -1-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-16- [1-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] -7-ethyl -5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 16- [2- (2-Aminomethyl-thiazol-4-yl) -1-fluorovinyl] -4,8-dihydroxy-7-ethyl-5 , 5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-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; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-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] heptadecane-5,9-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-thiazol-4-yl) -1-fluorovinyl] -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 (Z)) - 4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-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-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 16- [2- (2-Aminomethyl-thiazol-4-yl) -1-chloro vinyl] -4,8-dihydroxy-7-ethyl-5 , 5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-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; (1S, 3S (Z), 7S, 10R, 11S, 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] heptadecane-5,9-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-thiazol-4-yl) -1-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- [1-methyl-2- (2-pyridyl) - vinyl] -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-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- [1-methyl-2- (2-pyridyl ) vinyl] -oxacyclohexadec-l3-en-2,6-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-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- [1-fluoro-2- (2-pyridyl) - vinyl] -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-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- [1-chloro-2- (2-pyridyl) - vinyl] -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-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- [1-fluoro-2- (2-pyridyl ) -vinyl] -oxacyclohexadec-13-ene-2,6-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-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-L6 [1-chloro-2- (2-pyridyl ) -vinyl] -oxacyclohexadec-13-ene-2,6-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- (1-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- [1-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) -1-methyl-vinyl] -5,5,7 , pen-9.13 tamethyl-oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 16- [2- (2-Aminomethyl-oxazol-4-yl) -1-methyl vinyl] -4,8-dihydroxy-5,5,7 , 9,13-pentamethyl-oxacyclohexadec-13-en-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 oxazole-4-yl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- [2- (2-hydroxymethyl-oxazol-4-yl) -1-methyl-vinyl] -8,8 , 10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (E), 7S, 10R, 11 S, 12S, 16R) -3- [2- (2-aminomethyl-oxazol-4-yl) -1-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- [1-methyl-2- (2-methyl oxazole-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) -1-methyl-vinyl] -7-ethyl -5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 16- [2- (2-Aminomethyl-oxazol-4-yl) -1-methyl vinyl] -4,8-dihydroxy-7-ethyl-5 , 5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-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; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2- (2-hydroxymethyl-oxazol-4-yl) -1-methyl-vinyl] -10-ethyl -8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (E), 7S, 10R, 11S, 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] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [ 1-fluoro-2- (2-methyl-oxazol-4-yl) vinyl] oxacyclohexadec-13-en-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) -1-fluorovinyl] -4,8-dihydroxy-5 , 5,7,9,13-pentamethyl-oxacyclohexadec-13-en-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-oxazol-4-yl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecane-5, 9-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2- (2-hydroxymethyloxazo l-4-yl) -1-fluoro-vinyl] -8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-oxazol-4-yl) -1-fluorovinyl] -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- [1-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) -1-chloro-vinyl] -5,5 , 7,9,13--pentamethyl-oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 16- [2- (2-Aminomethyl-oxazol-4-yl) -1-chloro vinyl] -4,8-dihydroxy-5,5,7 , 9,13-pentamethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-chloro-2- (2-methyl oxazole-4-yl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-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; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-oxazol-4-yl) -1-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-16- [1-fluoro-2- (2-methyl oxazole-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-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 16- [2- (2-Aminomethyl-oxazol-4-yl) -1-fluorovinyl] -4,8-dihydroxy-7-ethyl-5 , 5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-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, 11S, 12S, 16R) -7,11-Dihydroxy-3- [2- (2-hydroxymethyl-oxazol-4-yl) -1-fluoro-vinyl] -10-ethyl -8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-oxazol-4-yl) -1-fluorovinyl] -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 (Z)) - 4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-chloro-2- (2-methyl oxazole-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-chloro-vinyl] -7-ethyl -5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 16- [2- (2-Aminomethyl-oxazol-4-yl) -1-chloro vinyl] -4,8-dihydroxy-7-ethyl-5 , 5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-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; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-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] heptadecane-5,9-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-oxazol-4-yl) -1-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- [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-en-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-en-2,6-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-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; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-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; (1S, 3S (E), 7S, 10R, 11S, 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-l3-en-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-en-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-en-2,6-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-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) -7,11-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; (1S, 3S (E), 7S, 10R, 11S, 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; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-8,8,10,12,16-penta methyl-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; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-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-16- (2-methyl-benzothiazol-5-yl) -oxacyclohexadec-13 en-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- en-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- en-2,6-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-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) -7,11-Dihydroxy-3- (2-hydroxymethylbenzothiazol-5-yl) -8,8,10,12,16-pentamethyl-4,17- dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzothiazol-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-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; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-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; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethylbenzothiazol-5-yl) -10-ethyl-8,8,12,16-tetramethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 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-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-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; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-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) -7,11-Dihydroxy-3- (2-hydroxymethylbenzothiazol-5-yl) -10-propyl-8,8,12,16-tetramethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 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-16- (2-hydroxymethyl-benzothiazol-5-yl) -7-butyl-5,5,9,13-tetramethyl-oxacyclohexadec- l3-en-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; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-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) -7,11-Dihydroxy-3- (2-hydroxymethylbenzothiazol-5-yl) -10-butyl-8,8,12,16-tetramethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzothiazol-5-yl) -7,11-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- 13-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; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-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) -7,11-Dihydroxy-3- (2-hydroxymethylbenzothiazol-5-yl) -10-allyl-8,8,12,16-tetramethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzothiazol-5-yl) -7,11-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-ynyl-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-ynyl-5,5,9,13- tetramethyl-oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-Aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-prop-2-ynyl-5,5,9,13- tetramethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-prop-2-ynyl-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) -7,11-Dihydroxy-3- (2-hydroxymethylbenzothiazol-5-yl) -10-prop-2-ynyl-8,8,12,16- tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-prop-2-ynyl-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-en-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- tetrameth yl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-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) -7,11-Dihydroxy-3- (2-hydroxymethylbenzothiazol-5-yl) -10-but-3-enyl-8,8,12,16- tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 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-ynyl-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-ynyl-5,5,9,13- tetramethyl-oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-Aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-but-3-ynyl-5,5,9,13- tetramethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-but-3-ynyl-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) -7,11-Dihydroxy-3- (2-hydroxymethylbenzothiazol-5-yl) -10-but-3-ynyl-8,8,12,16- tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 12S, 16R) -3- (2-Aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-but-3-ynyl-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 en-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- en-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- en-2,6-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-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) -7,11-dihydroxy-3- (2-hydroxymethylbenzoxazol-5-yl) -8, 8,10,12,16-pentamethyl-4,17- dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-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) -7,11-Dihydroxy-3- (2-hydroxymethylbenzoxazol-5-yl) -10-ethyl-8,8,12,16-tetramethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzoxazol-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-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; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-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) -7,11-Dihydroxy-3- (2-hydroxymethylbenzoxazol-5-yl) -10-propyl-8,8,12,16-tetramethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzoxazol-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-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-oxa cyclohexadec-13-ene-2,6-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-butyl-8,8,12,16-tetramethyl-3- (2-methyl-benzoxazol-5-yl) - 4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethylbenzoxazol-5-yl) -10-butyl-8,8,12,16-tetramethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzoxazol-5-yl) -7,11-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) -7,11-Dihydroxy-3- (2-hydroxymethylbenzoxazol-5-yl) -10-allyl-8,8,12,16-tetramethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzoxazol-5-yl) -7,11-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-ynyl-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-ynyl-5,5,9,13- tetramethyl-oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-Aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-prop-2-ynyl-5,5,9,13- tetramethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-prop-2-ynyl-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) -7,11-Dihydroxy-3- (2-hydroxymethylbenzoxazol-5-yl) -10-prop-2-ynyl-8,8,12,16- tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-prop-2-ynyl-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-I3-en-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-en-2,6-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-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) -7,11-Dihydroxy-3- (2-hydroxymethylbenzoxazol-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, 10R, 11 S, 12S, 16R) -3- (2-aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-but-3-enyl-8,8, 12,16-tetramethyl-4,17-dioxabicyclo (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-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z , 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-but-3-ynyl-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-ynyl-5,5, 9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-but-3-ynyl-8, 8,12,16-tetramethyl-3- (2-methyl-benzoxazol-5-yl) -4,17-dioxabicyclo [14.1.0] heptadecan-5,9-dione; (1S, 3S, 7S, 10R, 11 , 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethylbenzoxazol-5-yl) -10-but-3-ynyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [ 14.1.0] heptadecan-5,9-dione; (1S, 3S, 7S, 10R, 11 S, 12S, 16R) -3- (2-aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10 -but-3-ynyl-8,8,12,16-tetramethyl-4,17- dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, where the hydrogen atoms in the abovementioned effector bases are replaced by radicals L 1 -L 3 at the positions indicated in formula (1). Effektor-Konjugat gemäß einem der Ansprüche 1-3, wobei der Linker ausgewählt ist aus der Gruppe bestehend aus Verbindungen der allgemeinen Formel (III), wobei V eine Bindung oder einen Arylrest darstellt, o Null ist, und T ein Sauerstoffatom ist.Effector conjugate according to one of claims 1-3, with the linker selected is from the group consisting of compounds of the general formula (III), where V represents a bond or an aryl radical, O Is zero, and T is an oxygen atom. Effektor-Erkennungseinheit-Konjugat der allgemeinen Formel (1),
Figure 00800001
wobei die Substituenten darin die in Anspruch 1 genannten Bedeutungen haben, jedoch mindestens eine Gruppe FG1 durch eine Gruppe FG2 ersetzt ist, wobei FG2 die folgenden Bedeutungen haben kann:
Figure 00800002
wobei eine Erkennungseinheit über ein Schwefelatom mit der Gruppe FG2 konjugiert ist; wobei die Erkennungseinheit ausgewählt ist aus der Gruppe bestehend aus Peptiden, löslichen Rezeptoren, Cytokinen, Lymphokinen, Aptameren, Spiegelmeren, rekombinanten Proteinen, neuen Framework-Strukturen, monoklonalen Antikörpern, und Fragmenten monoklonaler Antikörper; als einheitliches Isomer oder eine Mischung unterschiedlicher Isomere und/oder als ein pharmazeutisch akzeptables Salz hiervon.Effector-recognition unit conjugate of the general formula (1),
Figure 00800001
wherein the substituents therein have the meanings given in claim 1, but at least one group FG 1 has been replaced by a group FG 2 , where FG 2 can have the following meanings:
Figure 00800002
wherein a recognition unit is conjugated to the group FG 2 via a sulfur atom; wherein the recognition unit is selected from the group consisting of peptides, soluble receptors, cytokines, lymphokines, aptamers, Spiegelmeres, recombinant proteins, new framework structures, monoclonal antibodies, and fragments of monoclonal antibodies; as a uniform isomer or a mixture of different isomers and / or as a pharmaceutically acceptable salt thereof. Effektor-Erkennungseinheit-Konjugat gemäß Anspruch 5, wobei das Konjugat mehr als eine Erkennungseinheit enthält, und wobei die Erkennungseinheiten identisch sind.The effector recognition unit conjugate according to claim 5, wherein the conjugate contains more than one recognition unit, and wherein the recognition units are identical. Effektor-Erkennungseinheit-Konjugat gemäß Anspruch 5 oder 6, wobei die Erkennungseinheit ein Antikörper ist, oder ein antigen-bindendes Fragment desselben, welcher für ein Antuigen spezifisch ist, das ausgewählt ist aus der Gruppe bestehend aus den in Tabelle 1 aufgeführten Antigenen, sowie CD19, CD20, CD40, CD22, CD25, CDS, CD52, CD10, CD2, CD7, CD33, CD38, CD40, CD72, CD4, CD21, CD37, CD30, VCAM, CD31, ELAM, Endoglin, VEGFRI/II, αvβ3, Tie1/2, TES23 (CD44ex6), Phosphatidylserin, PSMA, VEGFR/VEGF-Komplex und ED-B-Fibronectin.The effector-recognition unit conjugate according to claim 5 or 6, wherein the recognition unit is an antibody, or an antigen-binding fragment thereof, which is specific for an antigen selected from the group consisting of the antigens listed in Table 1, and CD19 , CD20, CD40, CD22, CD25, CDS, CD52, CD10, CD2, CD7, CD33, CD38, CD40, CD72, CD4, CD21, CD37, CD30, VCAM, CD31, ELAM, Endoglin, VEGFRI / II, α v β 3 , Tie1 / 2, TES23 (CD44ex6), phosphatidylserine, PSMA, VEGFR / VEGF complex and ED-B fibronectin. Linker der allgemeinen Formel (III1:
Figure 00810001
worin RG1 eine O=C=N-Gruppe oder eine S=C=N-Gruppe ist, und o, V, q und FG1 die in Anspruch 1 genannten Bedeutungen haben; oder Linker der allgemeinen Formel (III2):
Figure 00820001
worin RG2 eine Hal-C(=T)-CHR22-Gruppe oder eine Hal-C(=T)-CHR22-NR23-C(=T)-Gruppe oder eine R26-C(=O)-O-C(=T)-CHR22-Gruppe oder eine R26-C(=O)-O-C(=T)-CHR22-NR23-C(=T)-Gruppe ist, wobei R26 C1-C10 Alkyl, Aryl, Aralkyl ist, und o, V, q und FG1 die in Anspruch 1 genannten Bedeutungen haben; oder Linker der allgemeinen Formel (III3):
Figure 00820002
worin RG3 eine OH-Gruppe oder eine NHR24a-Gruppe oder eine COOH-Gruppe ist, und o, V, q und FG1 die in Anspruch 1 genannten Bedeutungen haben; jedoch mit der Bedingung, dass die Verbindung 1-(4-Amino-phenyl)-pyrrol-2,5-dion nicht umfasst ist.Linker of the general formula (III 1 :
Figure 00810001
wherein RG 1 is an O = C = N group or an S = C = N group, and o, V, q and FG 1 have the meanings given in claim 1; or linker of the general formula (III 2 ):
Figure 00820001
wherein RG 2 is a Hal-C (= T) -CHR 22 group or a Hal-C (= T) -CHR 22 -NR 23 -C (= T) group or one R 26 -C (= O) -OC (= T) -CHR 22 group or an R 26 -C (= O) -OC (= T) -CHR 22 -NR 23 -C (= T) group , wherein R 26 is C 1 -C 10 alkyl, aryl, aralkyl, and o, V, q and FG 1 have the meanings given in claim 1; or linker of the general formula (III 3 ):
Figure 00820002
wherein RG 3 is an OH group or an NHR 24a group or a COOH group, and o, V, q and FG 1 have the meanings given in claim 1; however, provided that the compound 1- (4-aminophenyl) pyrrole-2,5-dione is not included. Linker gemäß Anspruch 8, wobei V eine Bindung oder einen Arylrest darstellt, o gleich Null ist und T ein Sauerstoffatom ist.Linker according to claim 8, where V represents a bond or an aryl radical, o is the same Is zero and T is an oxygen atom. Verfahren zur Herstellung von Effektor-Konjugaten gemäß einem der Ansprüche 1–4, wobei eine Verbindung der allgemeinen Formel (I), wobei die Substituenten die in Anspruch 1 genannten Bedeutungen haben, jedoch die Bedingung, das mindestens ein Substituent L1, L2 oder L4 einen Linker der allgemeinen Formel (III) darstellt, nicht erfüllt sein muß, und mindestens ein Substituent L1, L2 oder L4 Wasserstoff, eine Gruppe C(=O)Cl, oder eine Gruppe C(=S)Cl darstellt; mit einem Linker, der ausgewählt ist aus der Gruppe bestehend aus einem Linker der allgemeinen Formel (III1) oder (III2) oder (III3), wie in Anspruch 8 beschrieben, umgesetzt wird.A process for the preparation of effector conjugates according to any one of claims 1-4, wherein a compound of general formula (I), wherein the substituents have the meanings given in claim 1, but the condition that at least one substituent L 1 , L 2 or L 4 represents a linker of the general formula (III), need not be satisfied, and represents at least one substituent L 1 , L 2 or L 4 hydrogen, a group C (= O) Cl, or a group C (= S) Cl ; with a linker selected from the group consisting of a linker of the general formula (III 1 ) or (III 2 ) or (III 3 ) as described in claim 8. Verfahren zur Herstellung von Effektor-Erkennungseinheit-Konjugaten gemäß einem der Ansprüche 5 bis 7, wobei ein Effektor-Konjugat gemäß einem der Ansprüche 1–4 mit mindestens einer Erkennungseinheit, wie in Anspruch 5 und 7 definiert, umgesetzt wird.Process for the preparation of effector recognition unit conjugates according to one of claims 5 to 7, wherein an effector conjugate according to any one of claims 1-4 with at least a recognition unit, as defined in claims 5 and 7, implemented becomes. Verwendung einer Verbindung der allgemeinen Formel (I), wobei die Substituenten die in Anspruch 1 genannten Bedeutungen haben, jedoch die Bedingung, dass mindestens ein Substituent L1, L2 oder L4 einen Linker der allgemeinen Formel (III) darstellt, nicht erfüllt sein muß, und mindestens ein Substituent L1, L2 oder L4 Wasserstoff, eine Gruppe C(=O)Cl, oder eine Gruppe C(=S)Cl darstellt; in einem Verfahren gemäß Anspruch 10.Use of a compound of the general formula (I), where the substituents have the meanings given in claim 1, but the condition that at least one substituent L 1 , L 2 or L 4 is a linker of the general formula (III) is not met must, and at least one substituent L 1 , L 2 or L 4 represents hydrogen, a group C (= O) Cl, or a group C (= S) Cl; in a method according to claim 10. Verwendung einer Verbindung der allgemeinen Formel (I) zur Herstellung eines Effektor-Erkennungseinheit-Konjugats gemäß den Ansprüchen 5 bis 7.Use of a compound of general formula (I) for the preparation an effector-recognition unit conjugate according to claims 5 to 7. Verwendung eines Linkers der allgemeinen Formel (III1), (III2) oder (III3) in einem Verfahren gemäß Anspruch 10.Use of a linker of the general formula (III 1 ), (III 2 ) or (III 3 ) in a process according to claim 10. Verwendung eines Linkers der allgemeinen Formel (III1), (III2) oder (III3) zur Herstellung eines Effektor-Erkennungseinheit-Konjugats gemäß einem der Ansprüche 5 bis 7.Use of a linker of the general formula (III 1 ), (III 2 ) or (III 3 ) for the production of an effector-recognition unit conjugate according to one of Claims 5 to 7. Verwendung einer Erkennungseinheit, wie in Anspruch 5 oder 7 definiert, in einem Verfahren gemäß Anspruch 11.Use of a recognition unit as in claim 5 or 7 defined in a method according to claim 11. Effektor-Erkennungseinheit-Konjugat gemäß einem der Ansprüche 5 bis 7 zur Verwendung als Medikament.Effector-recognition unit conjugate according to one of claims 5 to 7 for use as a medicament. Effektor-Erkennungseinheit-Konjugat gemäß einem der Ansprüche 5 bis 7 zur Verwendung als Medikament zur Behandlung von Erkrankungen, die mit proliferativen Prozessen assoziiert sind.Effector-recognition unit conjugate according to one of claims 5 to 7 for use as a medicament for the treatment of diseases, associated with proliferative processes. Effektor-Erkennungseinheit-Konjugat gemäß einem der Ansprüche 5 bis 7 zur Verwendung als Medikament zur Behandlung einer Krankheit, die ausgewählt ist aus der Gruppe bestehend aus Tumoren, entzündlichen Erkrankungen, neurodegenerativen Erkrankungen, Angiogenese-assoziierten Erkrankungen, Multipler Sklerose, Alzheimer, und rheumatoider Arthritis.Effector-recognition unit conjugate according to one of claims 5 to 7 for use as a medicament to treat a disease, the selected is from the group consisting of tumors, inflammatory diseases, neurodegenerative Diseases, angiogenesis-associated diseases, multiple sclerosis, Alzheimer's and rheumatoid arthritis.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005074901A2 (en) * 2004-01-30 2005-08-18 Schering Ag New effector conjugates, process for their production and their pharmaceutical use

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005074901A2 (en) * 2004-01-30 2005-08-18 Schering Ag New effector conjugates, process for their production and their pharmaceutical use
WO2005074901A3 (en) * 2004-01-30 2006-03-30 Schering Ag New effector conjugates, process for their production and their pharmaceutical use

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8127 New person/name/address of the applicant

Owner name: BAYER SCHERING PHARMA AG, 13353 BERLIN, DE

8127 New person/name/address of the applicant

Owner name: BAYER SCHERING PHARMA AKIENGESELLSCHAFT, 13353, DE

8141 Disposal/no request for examination