CA2492437A1 - New effector conjugates, process for their production and their pharmaceutical use - Google Patents

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

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CA2492437A1
CA2492437A1 CA002492437A CA2492437A CA2492437A1 CA 2492437 A1 CA2492437 A1 CA 2492437A1 CA 002492437 A CA002492437 A CA 002492437A CA 2492437 A CA2492437 A CA 2492437A CA 2492437 A1 CA2492437 A1 CA 2492437A1
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dione
dihydroxy
tetramethyl
methyl
oxacyclohexadec
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French (fr)
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Markus Berger
Gerhard Siemeister
Ulrich Klar
Joerg Willuda
Andreas Menrad
Klaus Bosslet
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Bayer Pharma AG
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Individual
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Priority claimed from DE10234975A external-priority patent/DE10234975A1/en
Priority claimed from DE10305098A external-priority patent/DE10305098A1/en
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Publication of CA2492437A1 publication Critical patent/CA2492437A1/en
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Abstract

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

Description

New Effector Conjugates, Process for their Production and their Pharmaceutical Use The development of the understanding relating to the recognition of binding regions, especially in the field of monoclonal antibodies or fragments thereof against specific tumor antigens, makes it possible to consider a selective tumor therapy by specific release of an anti-tumor active agent at the target site.
A precondition for such an approach, in which a highly active (toxic) active to agent (effector) is coupled to a high-molecular, tumor-specific recognition unit, such as, for example, to an antibody, is a substantial inactivity of the conjugate, whose minimum components are represented by a recognition unit and an effector, until it has reached the target site (tumor). Arriving at the target site, the conjugate binds to the cell surface and the active ingredient, optionally after the preceding internalization of 15 the entire complex, can be released.
The successful therapy of solid tumors, especially with monoclonal antibodies, can be limited, however, by an inadequate penetration of the antibody into the tumor as well as the heterogeneous dispersion of the corresponding tumor-associated antigens in the tumor tissue.
20 These limitations could be avoided in that the tumor-vascular system is attacked in a specific way. The growth of tumors below a volume of about 2 mm3 depends on a neoangiogenesis. The subsequent tumor growth is based on an intact vascular system, which ensures the supply with nutrients or the removal of waste products. The selective destruction of this system should therefore result in a necrosis 25 of the tumor. The attack on the vascular system of the tumor promises a number of advantages relative to the direct attack on the tumor itself. In comparison to tumor cells, endothelial cells are easier to access, since no tumor tissue has to be penetrated.
The damage of an individual tumor vessel should result in a necrosis of thousands of tumor cells. To damage a tumor vessel, it is not necessary to kill all endothelial cells.
3o The specific attack of endothelial cells in or close to the tumors minimizes systemic side effects. Endothelial cells are genetically very stable, so that the probability of a development of resistance against the tumor therapeutic agent is low.

~ ?f ~.n ~ ~I' .
~~e ~ 9.
i. a ~ ~ ~' .u.sm"i~F~~.. as 'F., x Z
Within the scope of this invention, surprisingly enough, a possibility has now been found to link the chemically very sensitive, highly-functionalized class of active agents of epothilones and analogs thereof to a high-molecular recogiition unit via different linkers in different positions of the active agent.
The object of this invention is thus, inter alia, 1, to find a method to link highly active active agents fronr~ the structural class of the epothilones and epothilone derivatives to suitable linkers, 2. to synthesize suitable linkers, 3. to develop a method to link these epothilona-linker conjugates to recognition units, such as, for example, monoclonal antibodies or fragnents thereof, to form immune conjugates that are both chemically and metabolically sufficiently stable for the development of a pharmaceutical, and that are superior to the epothilones or epothilone derivatives that are taken as a basis with respect to their therapeutic range, their selectivity of action and/or undesirable toxic side effects and/or the degree of their activity.
This invention accordingly comprises effector conjugates of general formula I
Rs R
R' ~E~
R4a R3 O_~2 ~a R4b R1D
\~ ~.R2D
L' z irt which Rl a~ ~lb~ independently of one another, are hydrogen, C1-C10 alkyl, aryl, aralkyl, or together a -(CH2),n goup, in which m is 2 to 5, R2a~ R2b~ independently of one another, are hydrogen, C1-C10 alkyl, aryl, aralkyl, or together a-{CH2)n group, in which n is 2 to 5, or C2-C10 .',1,5 AMENDED SHEET

~~r'~ 1~ p t ~'~ p '~~L
,, .. I , . x alkenyl, or C2-C l0 alkynyl, a R3 is hydrogen, C 1-C 1 p alkyl, aryl or aralkyl, and R4a~ R4b~ independently of one another, are hydrogen, C 1-C 10 alkyl, aryl, aralkyl, or together a -(CH2)p group, in which p is 2 to 5, RS is hydrogen, C1-Cl0 alkyl, aryl, aratkyl, C02H, C02alkyt, CH20H, CH20Alkyl, CHZOAcyI, CN, CH2NH2, CH2N(alkyl, acyl)1~2, or CHZHaI, Hal is a halogen atom, R6, R~ in each cas~are hydrogen, or together an additional bond, or together an oxygen atom, or together an NH group, or together an N-alkyl group, or together a CH2 group, and G is an oxygen atom or CH2, D-E is a group H2C-CH2, HGCH, C~C, CH(OH)-CH(OH), CH(O>:~-CH2, O
CH2-CH(OH), HC CH ~ O-CHZ, or, if G represents a CH2 group, D-E is also CH2-O, W is a group C(=X)Rg, or a bi- or tricyclic aromatic or heteroaromatic radical, L3 is hydrogen, or, if a radical in W contains a hydroxyl group, forims a group O-L4 with the latter, or, if a radical in W contains an amino group, forms a group NR25-L4 with the latter, R25 is hydrogen or C 1-C 10 alkyl, AMENDED SHEET
X is an oxygen atom, or two OR20 groups, or a C2-C 10 alkylenedioxy group that may be straight-chain or branched, or H/OR9, or a CR10R11 group, Rg is hydrogen, C1-C10 alkyl, aryl, aralkyl, halogen or CN, and R9 is hydrogen or a protective group PGX, R10~ Rl l in each case independently of one another, are hydrogen, C1-C20 alkyl, aryl, aralkyl, or together with a methylene carbon atom form a 5- to 7-membered carbocyclic ring, Z can represent oxygen or H/ORl ~, R12 can represent hydrogen or a protective group PGZ, A-Y can represent a group O-C(=O), O-CH2, CH2-C(=O), NR21-C(=O) or NR21-502, R20 can represent C1-C2p alkyl, R21 can represent a hydrogen atom or C1-C10 alkyl, PGX, PGY, and PGZ can represent a protective group PG, and L1, L2, and L4, independently of one another, can represent hydrogen, a group C(=O)Cl, a group C(=S)Cl, a group PGY or a linker of general formula (III) or (IV);
provided that at least one substituent Ll, L2 or L4 represents a linker of general formula (III) or (IV);
the linker of general formula (III) has the following structure, T
'U CH -V- CH -FGA
( 2)0 ~ 2)q in which T can represent oxygen or sulfur, U can represent oxygen, CHR22, CHR22-NR23-C(=O)-, CHR22-NR23_ C(=S)-, O-C(=O)-CHR22-NR23-C(=O)-, O-C(=O)-CHR22-NR23-5 C(=S)- or NR24a, o can represent 0 to 15, V can represent a bond, aryl, a group N R2ab-C(=O)-O-(CH2)S
Q-or a group NR24b-C(=S)-O-(CFi2)S _ to Q , s can represent 0 to 4, Q can represent a bond, O-C(=O)-NR24c, O-C(=S)-NR24c~
-O-C(=O)-NR2a.o - _p_C(=S)-NR24 _~\~ , o --~'-=~r R22 can represent hydrogen, C1-C10 alkyl, aryl or aralkyl, is R23 can represent hydrogen or C1-C10 alkyl, R24a~ R24b~ ~d R24c~ independently of one another, can represent hydrogen or C 1-C 10 alkyl, q can represent 0 to 15, FG1 can represent Cl-Clp alkyl-S3, o , , , , _S~
or C02H; and the linker of general formula (IV) has the following structure, R2' T
~W~ CH IV, ( 2)0 \
(CH2)q W2 C(=O)-U--(CH2)~ FGA
s in which T can represent oxygen or sulfur, Wl, W2 are the same or different and can represent oxygen or NR24a, o can represent 0 to 5, 1o R2~ can represent hydrogen, CI-Cio alkyl, aryl or aralkyl, R~3 can represent hydrogen, or Ci-Cio alkyl, R24a c~ represent hydrogen or C1-Clo alkyl, Ra7 can represent halogen, CN, N02, CO2R2$, or OR2g, R~'8 can represent hydrogen, C1-Cio alkyl, aryl or aralkyl, 1 s q can represent 0 to 5, LT can represent oxygen, CHRaa, CHR~'a-NR23-C(=O)-, CHR2a-NR23-C(=S)-or C1-Coo alkyl, r can represent 0 to 20, 2o FGl can represent C1-CIO alkyl-S3, N ~ O ~ -S!/
I I
o , ~ ~ sr ~ ci ~ o , or C02H, as a single isomer or a mixture of different isomers and/or as a pharmaceutically acceptable salt thereof.
In addition, the invention describes the production of effector recognition unit conjugates of general formula (I), wherein the substituents therein have the above-mentioned meanings, but at least one group FGl is replaced by a group FG2a or FG2b, wherein FG~a or FGab can have the following meanings:

o ° o s ~ ~ -n~
° ~S~ ~S~ S
a~ o ~s~ IBr cl o FG : -S-S-, , , , FGab: -CONH-l0 and wherein a recognition unit is conjugated via a sulfur atom with the group FG2a, wherein the indicated sulfur atom is a component of the recognition unit, or via an amide function of group FG2b, wherein the indicated nitrogen atom is a component of the recognition unit;
wherein the recognition unit can be, for example, a peptide, a soluble receptor, a cytokine, a lymphokine, an aptamer, a spiegelmer, a recombinant protein, a framework structure, a monoclonal antibody or a fragment of a monoclonal antibody.
According to this invention, the above-mentioned effector recognition unit conjugates can comprise one or more recognition units; in this case, the recognition units that belong to a conjugate can be identical or different. It is preferred that the 2o recognition units of a conjugate be identical.
The effector recognition unit conjugates according to the invention can be used in the form of their a-, (3- or y-cyclodextrin-clathrates or in the form of liposomal or pegylated compositions.
The conjugates according to the invention are preferably used for the treatment of diseases that are associated with proliferative processes. For example, the therapy of different tumors, the therapy of inflammatory and/or neurodegenerative diseases, such as multiple sclerosis or Alzheimer's disease, the therapy of angiogenesis-associated diseases such as the growth of solid tumors, rheumatoid arthritis or diseases of the ocular fundus, can be mentioned.
The production of epothilones, their precursors and derivatives of general formula I is carried out according to the methods that are known to one skilled in the art, as they are described in, for example, DE 19907588, WO 98/25929, WO
99/58534, WO 99/2514, WO 99/67252, WO 99/67253, WO 99/7692, EP 99/4915, WO 00/485, WO 00/1333, WO 00/66589, WO 00/49019, WO 00/49020, WO 00/49021, WO
00/71521, WO 00/37473, WO 00/57874, WO 01/92255, WO 01/81342, WO
01/73103, WO 01/64650, WO 01/70716, US 6204388, US 6387927, US 6380394, US
02/52028, US 02158286, US 02/62030, WO 02/32844, WO 02/30356, WO 02132844, WO 02/14323, and WO 02/8440.
As alkyl groups Rla, Rlb~ R2a~ R2b~ R3~ R4a~ R4b~ R5~ R8~ R10~ Rl l~ R20 R21, R22, R23, R24a, R24b~ R24c~ R25 ~d R26~ straight-chain or branched-chain alkyl groups with 1-20 carbon atoms can be considered, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, and decyl.
Alkyl groups Rla, Rlb, R2a, R2b, R3, R4a, R4b~ R5~ R8~ R10~ Rl l~ R20~ R21 R22~ R23~ R24a~ R24b~ R24c~ R25 ~d R26 c~ also be perfluorinated or substituted by 1-5 halogen atoms, hydroxy groups, Cl-C4-alkoxy groups or C6-C12-aryl groups (which can be substituted by 1-3 halogen atoms).
As aryl radicals Rla, Rlb, R2a, R2b, R3, R4a, R4b~ R5~ R8~ R10~ Rl l~ R22 R26 and V, substituted and unsubstituted carbocyclic or heterocyclic radicals with one or more heteroatoms, such as phenyl, naphthyl, fiuyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl, benzothiazolyl or benzoxazolyl, which can be substituted in one or more places by halogen, OH, O-alkyl, C02H, C02-alkyl, -NH2, -N02, -N3, -CN, Cl-C20-alkyl, C1-C20-acyl or C1-C20' acyloxy groups, are suitable. The heteroatoms can be oxidized provided that this does not cause the aromatic character to be lost, such as, for example, the oxidation of a pyridyl to a pyridyl-N-oxide.
As bicyclic and tricyclic aryl radicals W, substituted and unsubstituted, carbocyclic or heterocyclic radicals with one or more heteroatoms such as naphthyl, anthryl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolyl, isoquinolyl, benzoxazinyl, benzofuranyl, indolyl, indazolyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thienopyridinyl, pyridopyridinyl, benzopyrazolyl, benzotriazolyl, or dihydroindolyl, which can be substituted in one or more places by halogen, OH, O-alkyl, C02H, C02-alkyl, -NH2, -N02, -N3, -CN, Cl-C20-alkyl, C1-C20-acyl or C1-C20-acyloxy groups, are suitable. The heteroatoms can be oxidized provided that this does not cause the aromatic character to be lost, such as, for example, the oxidation of a quinolyl to a quinolyl-N-oxide.
The aralkyl groups in Rla, Rlb, R2a, R2b, R3, R4a~ R4b~ R5~ R8~ R10~ Rll R22 and R26 can contain in the ring up to 14 C atoms, preferably 6 to 10 C
atoms, and in the alkyl chain 1 to 8 atoms, preferably 1 to 4 atoms. As an aralkyl radical, for to example, benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl or pyridylpropyl is suitable. The rings can be substituted in one or more places by halogen, OH, O-alkyl, CO2H, CO2-alkyl, -N02, -N3, -CN, C1-C20-alkyl, C1-C20-aryl or Cl-C20-acyloxy groups.
As representatives of protective groups PG, tris(C1-C20 alkyl)silyl, bis(Cl-is alkyl)-arylsilyl, (C1-C20 alkyl)-diarylsilyl, tris(aralkyl)-silyl, C1-C20-alkyl, C2-C20-alkenyl, C4-C~-cycloalkyl, which in addition can contain an oxygen atom in the ring, aryl, C~-C20-aralkyl, C1-C20-acyl, aroyl, C1-C20-alkoxycarbonyl, C1-C20-alkylsulfonyl as well as arylsulfonyl can be cited.
As alkyl-, silyl- and acyl radicals for the protective groups PG, especially the 2o radicals that are known to one skilled in the art are considered. Preferred are the alkyl or silyl radicals that can be easily cleaved from the corresponding alkyl and silyl ethers, such as, for example, the methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert.-butyldimethylsilyl, tert.-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl, benzyl, 2s para-nitrobenzyl, and para-methoxybenzyl radicals, as well as alkylsulfonyl and arylsulfonyl radicals. As an alkoxycarbonyl radical, e.g., trichloroethyloxycarbonyl (Troc) is suitable. As an acyl radical, e.g., formyl, acetyl, propionyl, isopropionyl, trichloromethylcarbonyl, pivalyl, butyryl or benzoyl, which radical can be substituted with an amino and/or hydroxy group, is suitable.
3o As amino protective groups PG, the radicals that are known to one skilled in the art are suitable. For example, the Alloc, Boc, Z, benzyl, f Moc, Troc, stabase or benzostabase group can be mentioned.
As halogen atoms, fluorine, chlorine, bromine or iodine can be considered.

The acyl groups can contain 1 to 20 carbon atoms, formyl, acetyl, propionyl, isopropionyl and pivalyl groups being preferred.
The C2-C10-alkylene-a,e~-dioxy group that is possible for X is preferably an ethylene ketal or neopentyl. ketal group.
Preferred compounds of general formula I are those in which A-Y represents O-C(=O) or NR21-C(=O); D-E represents an H2C-CH2 group; G represents a CH2 group; Z represents an oxygen atom; Rla, Rlb in each case represent C1-C10 alkyl or together a -(CH2)p group with p equal to 2 or 3 or 4; R2a, R2b, independently of one another, 1 o represent hydrogen, C 1-C 10 alkyl, C2-C 10 alkenyl, or C2-C 10 alkynyl;
R3 represents hydrogen; R4a, R4b, independently of one another, represent hydrogen or C 1-C

alkyl; RS represents hydrogen, or C1-Cq. alleyl or CH20H or CH2NH2 or CH2N(alkyl, acyl) 1 ~2 or CH2Hal; R6 and R~ together represent an additional bond or together an NH group or together an N-alkyl group or together a CH2 group or together an oxygen is atom; W represents a group C(=X)Rg 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-hydroxyrnethylbenzoxazol-5-yl radical; X represents a CRlORl 1 group; Rg represents hydrogen or C1-C4 alkyl or a fluorine atom or a chlorine atom or a bromine atom; R10~11 represent hydrogen/2-methylthiazol-4-yl or hydrogen/2-pyridyl or hydrogenl2-methyloxazol-4-yl or hydrogen/2-aminomethylthiazol-4-yl or hydrogen/2-aminomethyloxazol-4-yl or hydrogen/2-hydroxymethylthiazol-4-yl or hydrogen/2-hydroxymethyloxazol-4-yl.
As linkers of general formula (III), compounds are preferred in which V
represents a bond or an aryl radical, o is equal to zero, and T represents an oxygen atom.
As linkers of general formula (III), in addition compounds are preferred in which V represents a bond or an aryl radical or a group NR2ab-C(=O)-O-(CH2)S
Q ; Q represents a bond or a group -O-C(=O)-N R24°-~~~
3o ; and o is 0 to 4. Especially preferred are compounds of general formula (III), wherein V represents a bond or a group .NR2ab-C(=~)-~_(CH2)S
Q ; Q represents a bond or a group -O-C(=O)-NR24°--~ .
o is equal to 0, 2 or 3; s is equal to 1; and T is an oxygen atom.
As linkers of general formula (IV), compounds are preferred in which o is zero to four, and q is zero to three. Especially preferred are compounds of general formula (IV), wherein o is 0, 2 or 3; Wl is an oxygen atom; q is equal to 0; R2a is hydrogen, C1 -C3 alkyl or aralkyl; R23 is hydrogen or C1-C3 alkyl; R24a 1S hydrogen or C1-C3 alkyl;
Ra7 is fluorine, chlorine, CN, NOa , COa R2$ or OR2g ; R2$ is hydrogen or CI -CS alkyl;
to and U is oxygen, CHR22 or CHR22 NR~3-C(=O)-.
As recombinant proteins for use as recognition units, for example, binding regions derived from antibodies, so-called CDRs, are suitable.
As framework structures for use as recognition units, for example, high-molecular structures that are not derived from antibodies are suitable. For example, 15 structures of the fibronectin type 3 and of crystallins can be mentioned.
As fragments of monoclonal antibodies for use as recognition units, for example, single-chain Fv, Fab, F(ab)2 as well as recombinant multimers can be mentioned.
As preferred recognition units, those are considered that are suitable for, for 2o example, the recognition and/or diagnosis and/or therapy of solid tumors and malignant diseases of the hematopoietic system.
As recognition units that are additionally preferred, those are considered that allow a selective recognition of the disease-specific vascular system, preferably of the angiogenesis.
25 Table 1 cites examples of especially preferred recognition units for treating solid tumors.

Tumor Antigen Identity/Monoclonal References Characteristics Antibodies Gynecol. CA 125' > 200 OC 125 Kabawat et al., (GY) kD 1983;
mucin GP Szymendera, 1986 Ovarian 80 Kd GP OC 133 Masuko et al., Cancer Res, 1984 Ovarian 'SGA' 360 Kd OMI de Krester et al., Ovarian High Mr mucin Mo vl Miotti et al., Cancer Res, Ovarian High Mr mucin/ Mo v2 Miotti et al., glycolipid Cancer Res, Ovarian NS 3C2 Tsuji et al., Cancer Res, Ovarian NS 4C7 Tsuji et al., Cancer Res, Ovarian High Mr mucin ID3 Gangopadhyay et al., Ovarian High Mr mucin DU-PAN-2 Lan et al., 1985 GY 7700 Kd GP F 36/22 Croghan et al., Ovarian 'gp 68' 48 Kd 4F7/7A10 Bhattacharya et GP al.,1984 Gy 40, 42kD GP OV-TL3 Poels et al., 1986 Gy 'TAG-72' High B72.3 Thor et al., 1986 Mr mucin WO 2004/012735, PCT/EP2003/008483 Tumor Antigen Identity!Monoclonal References Characteristics Antibodies Ovarian 300-400 Kd GP DF3 Kufe et al., 1984 Ovarian 60 Kd GP 2Cg/2F7 Bhattacharya et al., 1985 GY 105 Kd GP MF 116 Mattes et al., Ovarian 38-40 kD GP Movl8 Miotti et al., GY 'CEA' 180 Kd CEA 11-HS Wagener et al., Ovarian CA 19-9 or GICA CA 19-9 (1116NSAtkinson et al., 19-9) 1982 Ovarian 'FLAP' 67 Kd H17-E2 McDicken et al., Ovarian 72 Kd 791T/36 Perkins et al., Ovarian 69 Kd PLAP NDOG2 Sunderland et al., Ovarian unknown Mr PLAP H317 Johnson et al., Ovarian p185H~~ 4D5, 3H4, Shepard et al., 7C2, 1991 6E9, 2C4, 7F3, 2H11, 3E8, SBB, 7D3, SB8 Uterus, OvaryHMFG-2 HMFG2 Epenetos et al., GY HMFG-2 3.14.A3 Burchell et al., Breast 330-450 Kd GP DF3 Hayes et al., 1985 Breast NS NCRC-11 Ellis et al., 1984 Breast 37kD 3C6F9 Mandeville et al., Breast NS MBE6 Teramoto et al., Breast NS CLNHS Glassy et al., Tumor Antigen Identity/Monoclonal References Characteristics Antibodies Breast 47 Kd GP MAC 40/43 Kjeldsen et al., Breast High Mr GP EMA Sloane et al., Breast High Mr GP HMFG1 HFMG2 Arklie et al., Breast NS 3.15.C3 Arklie et al., Breast NS M3, M8, M24 Foster et al., Breast 1 (Ma) Blood M18 Foster et al., Group 1984 Ags Breast NS 67-D-11 Rasmussen et al., Breast Estrogen ReceptorD547Sp, D75P3,Kinsel et al., Breast EGF Receptor Anti EGF Sainsbury et al., Breast Laminine ReceptorLR-3 Horan Hand et al., Breast erb B-2 p185 TA1 Gusterson et al., Breast NS H59 Hendler et al., Breast 126 Kd GP 10-3D-2 Soule et al., 1983 Breast NS HmABl,2 Imam et al., 1984;
Schlom et al., Breast NS MBR 1,2,3 Menard et al., Breast 95 Kd 24-17-1 Thompson et al., Breast 100 Kd 24-17-2 (3E1-2)Croghan et al., Breast NS F36/22.M7/105Croghan et al., Breast 24 Kd C1 l, G3, Adams et al., 1983 Tumor Antigen Identity/Monoclonal References Characteristics Antibodies Breast 90 Kd GP B6-2 Colcher et al., Breast CEA & 180 Kd B1-1 Colcher et al., Breast Colon & pancreas,Cam 17-1 Imperial Cancer mucin-like Research Technology Ca 19-9 - MAb listing Breast Milk mucin, nuclearSM3 Imperial Cancer protein Research Technology Mab listing Breast Milk mucin, nuclearSM4 Imperial Cancer protein Research Technology Mab listing Breast Affinity-purifiedC-Mul (566) Imperial Cancer milk mucin Research Technology Mab listing Breast P185~~ 4D5 3H4, 7C2,Shepard et al., 6E9, 2C4, 7F3, 2H11, 3E8, SBB, 7D3, SB8 Breast CA 125 > 200 OC 125 Kabawat et al., Kd GP 1985 Breast High Mr mucin/ MO v2 Miotti et al., glycolipid Breast High Mr mucin DU-PAN-2 Lan et al., 1984 Tumor Antigen Identity/Monoclonal References Characteristics Antibodies Breast ' gp48' 48 Kd GP 4F7/7A10 Bhattacharya et al., 1984 Breast 300-400 Kd GP DF3 Kufe et al., 1984 Breast 'TAG-72' high B72-3 Thor et al., 1986 Mr mucin Breast 'CEA' 180 Kd cccccCEA 11 Wagener et al., Breast 'PLAP' 67 Kd H17-E2 McDicken et al., Breast HMFG-2 > 400 3-14-A3 Burchell et al., Kd GP 1983 Breast NS FO23C5 Riva et al., 1988 Colorectal TAG-72 High Mr B72-3 Colcher et al., mucin 1987 Colorectal GP37 (17-lA) 1038-17-Paul et al., 1986 lA

Colorectal Surface GP C017-lA LoBuglio et al., Colorectal CEA ZCE-025 Patt et al., 1988 Colorectal CEA AB2 Griffin et al., 1988a Colorectal Cell surface HT-29-15 Cohn et al., 1987 AG

Colorectal Secretory epithelium250-30.6 Leydem et al., Colorectal Surface glycoprotein44X14 Gallagher et al., Colorectal . NS A7 Takahashi et al., Colorectal NS GA73-3 Munz et al., 1986 Colorectal NS 791T/36 Farrans et al., Tumor Antigen Identity!Monoclonal References Characteristics Antibodies Colorectal Cell Membrane 28A32 Smith et al., 1987 &

Cytoplasmatic Ag Colorectal CEA & Vindesin 28.19.8 . Corvalen, 1987 Colorectal gp72 X MMCO-791 Byers et al., 1987 Colorectal high Mr mucin DU-PAN-2 Lan et al., 1985 Colorectal high Mr mucin ID3 Gangopadhyay et al., Colorectal CEA 180 I~d GP CEA 11-HS Wagener et al., Colorectal 60 Kd GP 2Cg/2F7 Bhattacharya et al., 1985 Colorectal CA-19-9 (or GICA)CA-19-9 Atkinson et al., (1116NS 19-9) Colorectal Lewis a PRSCS Imperial Cancer Research Technology Mab Listing Colorectal Lewis a PR4D2 Imperial Cancer Research Technology Mab Listing Colorectal Colon mucus PR4D1 Imperial Cancer Research Technology Mab Listing Melanoma P97a 4-1 Woodbury et al., Melanoma P97a 8-2 M17 Brown, et al., 1981a Tumor Antigen IdentitylMonoclonal References Characteristics Antibodies Melanoma P97b 96-5 Brown, et al., 1981a Melanoma P97~ 118-l, 133-2,Brown, et al., (113-2) 1981a Melanoma P97~ L1, L10, Rl0 Brown et al., 1981b (Rl9) Melanoma P97d I12 Brown et al., 1981b Melanoma P97e KS Brown et al., 1981b Melanoma P155 6-1 Loop et al., 1981 Melanoma GD3 disialogan- R24 Dippold et al., gliosides 1980 Melanoma P210, p60, p250 5-1 Loop et al., 1981 Melanoma P280 p440 225.285 Wilson et al., Melanoma GP 94, 75, 70 465.125 Wilson et al., & 25 1981 Melanoma P240-P250, P450 9-2-27 Reisfeld et al., Melanoma 100, 77, 75 Kd F11 Chee et al., 1982 Melanoma 94 Kd 376.965 Imai et al., 1982 Melanoma 4 GP Chains 465.125 Imai et al., 1982;
Wilson et al., 1981 Melanoma GP 74 15-75 Johnson & Reithmuller, Melanoma GP 49 15-95 Johnson & Reithmuller, Tumor Antigen Identity/Monoclonal References Characteristics Antibodies Melanoma 230 Kd Mel-14 Carrel et al., Melanoma 92 Kd Mel-12 Carrel et al., Melanoma 70 Kd Me3-TB7 Carrel et al., 1:387, 1982 Melanoma HMW MAA similar 225.28SD Kantor et al., to 1982 Melanoma HMW MAA similar 763.24TS Kantor et al., to 1982 Melanoma GP95 similar 705F6 Stuhlmiller et to 376- al., 1982 Melanoma GP125 436910 Saxton et al., Melanoma CD41 M148 Imperial Cancer Research Technology Mab listing Gastrointestinalhigh Mr mucin ID3 Gangopadhyay et al., (GI) 1985 Gallbladder,high Mr mucin DU-PAN-2 Lan et al., 1985 Pancreas, Stomach Pancreas NS OV-TL3 Poels et al., 1984 Pancreas, 'TAG-72' high B72-3 Thor et al., 1986 Mr Stomach, mucin Esophagus Tumor Antigen Identity/Monoclonal References Characteristics Antibodies Stomach ' CEA' 180 Kd GP CEA 11-HS Wagener et al.,1984 Pancreas HMFG-2 > 400 3-14-A3 Burchell et al.,1983 Kd GP

GI NS C COLI Lemkin et al.,1984 Pancreas, CA 19-9 (or GICA)CA-19-9 Szymendera, 1986 Stomach (1116NS 19-9) and CA50 Pancreas CA125 GP OC125 Szymendera, 1986 Lung p185H~~ 4D5, 3H4, Shepard et al., 7C2, 1991 Non-small-cell 6E9, 2C4, 7F3, lung cancer 2H11, 3E8, SBB, (NSCLC) 7D3, SB8 NSCLC high Mr MO v2 Miotti et al., mucin/glycolipid NSCLC 'TAG -72' high B72-3 Thor et al., 1986 Mr mucin NSCLC High Mr mucin DU-PAN-2 Lan et al., 1985 NSCLC 'CEA' 180 kD CEA 11-HS Wagener et al., Malignant Cytoplastic antigenMUG 8-22 Stavrou, 1990 that Glioma consists of 85HG-22 cells Tumor Antigen Identity/Monoclonal References Characteristics Antibodies Malignant Cell surface MUC 2-63 Stavrou, 1990 Ag that Glioma consists of 85HG-\63 cells Malignant Cell surface MUC 2-39 Stavrou, 1990 Ag that Glioma consists of 86HG-39 cells Malignant Cell surface MUG 7-39 Stavrou, 1990 Ag that Glioma consists of 86HG-39 cells Gl, Other P53 PAb 240, PAb Imperial Cancer 246, PAb 1801Research Technology MaB Listing Small, Round-Neural cell adhesionERIC-1 Imperial Cancer Cell Tumors molecules Research Technology MaB Listing Medulloblas- M148 Imperial Cancer tomas, Neuro- Research Technology blastomas, MaB Listing Rhabdomyo-sarcomas Tumor Antigen Identity/Monoclonal References Characteristics Antibodies Neuro- FMH25 Imperial Cancer blastomas Research Technology MaB Listing Kidneys & P155 6-1 Loop et al., 1981 Glioblastomas Bladders "Ca Antigen" CAl Ashall et al., & 350-390 1982 Laryngeal kD

Tumors NeuroblastomaGD2 3F8 Cheung et al., Prostate Gp48 48 kD GP 4F7/7Alp Bhattacharya et al., 1984 Prostate 60 kD GP 2Cg/2F7 Bhattacharya et al., 1985 Thyroid 'CEA' 180 kD CEA 11-HS Wagener et al., Prostata Neurocellin-2 2H8, lOG6 Berlex (NC-2), TMEFF2, TENB2, tomoregulin, As especially preferred recognition units for treating hematological tumors, antibodies or antibody fragments, such as CD19, CD20, CD40, CD22, CD25, CDS, CD52, CD10, CD2, CD7, CD33, CD38, CD40, CD72, CD4, CD21, CDS, CD37 and CD30, can also be mentioned.
As especially preferred recognition units for anti-angiogenic therapy, antibodies or fragments thereof, such as VCAM, CD31, ELAM, endoglin, VEGFRI/II, a~~33, Tiel/2, TES23 (CD44ex6), phosphatidylserine, PSMA, VEGFR/VEGF complex or ED-B-fibronectin, can be mentioned.

The compounds that are mentioned below are especially preferred according to the invention as effector elements:
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-5,5,7,9,13-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, ( 1 S,3 S(E),75,1 OR,11 S,125,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-to [l-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione, ( 1 S,3 S(E),75,1 OR,11 S,125,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-thiazol-4-yl)-1-methyl-vinyl]-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione, 15 (1S,3S(E),7S,lOR,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]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, 20 (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, ( 1 S, 3 S (E),7 S,1 OR,11 S,12 S,16R)-7,11-Dihydroxy-10-ethyl-8, 8,12,16-25 tetramethyl-3-[1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo [ 14.1.0]heptadecane-5,9-dione, ( 1 S,3 S(E),75, l OR,11 S,125,16R)-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]hepta-decane-5,9-dione, 30 (1S,3S(E),7S,lOR,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]hepta-decane-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, ( 1 S,3 S(Z),75,1 OR,11 S,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, to (1S,3S(Z),7S,lOR,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, ( 1 S,3 S(Z),75,1 OR,11 S,125,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-1-fluoro-vinyl]-7,11-dihydroxy-8, 8,10,12,16-pentamethyl-4,17-dioxa-15 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-pentamethyl-oxacyclohexadec-13-ene-2,6-dione, 20 (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, ( 1 S,3 S(Z),7 S,1 OR,11 S,125,16R)-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, 25 (1S,3S(Z),7S,lOR,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, ( 1 S,3 S (Z),75,1 OR,11 S,125,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-1-chloro-vinyl]-7,11-dihydroxy-8, 8,10,12,16-pentamethyl-4,17-dioxa-30 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-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, ( 1 S,3 S(Z),75,1 OR,11 S,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, ( 1 S,3 S(Z),75,1 OR,11 S,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-to bicyclo[14.1.0]hepta-decane-5,9-dione, (1 S,3 S(Z),75,1 OR,11 S,125,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-1-fluoro-vinyl]-7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]hepta-decane-5,9-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[1-15 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, 20 (1S,3S(Z),7S,lOR,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, (1 S,3 S(Z),7S,1 OR,11 S,125,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-thiazol-4-yl)-1-chloro-vinyl]-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-25 bicyclo[14.1.0]hepta-decane-5,9-dione, ( 1 S,3 S (Z),75,1 OR,11 S,125,16R)-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]hepta-decane-5,9-dione, (4S,7R,8 S,9S,13Z,16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[ 1-3o methyl-2-(2-pyridyl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione, ( 1 S,3 S (E),75,1 OR,11 S,125,16R)-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-13-ene-2,6-dione, ( 1 S,3 S(E),75,1 OR,11 S,125,16R)-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, ( 1 S,3 S(Z),75, l OR,11 S,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, ( 1 S,3 S(Z),75,1 OR,11 S,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, (1 S,3 S(Z),75,1 OR,11 S,125,16R)-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-16-[1-2o chloro-2-(2-pyridyl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione, ( 1 S,3 S (Z), 7 S, l OR,11 S,12 S,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]-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8 S,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, ( 1 S,3 S(E),75,1 OR,11 S,125,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3 [ 1-methyl-2-(2-methyl-oxazol-4-yl)-vinyl]-4,17-dioxa-bicyclo [ 14.1.0]
heptadecane-5,9-dione, ( 1 S,3 S (E),7 S, l OR,11 S,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, ( 1 S,3 S(E),75,1 OR,11 S,125,16R)-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-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-io 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, ( 1 S,3 S(E),75,1 OR,11 S,125,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3-[ 1-methyl-2-(2-methyl-oxazol-4-yl)-vinyl]-4,17-dioxa-is bicyclo[14.1.0]heptadecane-5,9-dione, ( 1 S,3 S(E),75,1 OR,11 S,125,16R)-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]hepta-decane-5,9-dione, ( 1 S,3 S(E),75, l OR,11 S,125,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-1-methyl-2o vinyl]-7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [ 14.1.0]hepta-decane-5,9-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[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-4-25 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, ( 1 S,3 S (Z),7 S,1 OR,11 S,125,16R)-7,11-Dihydroxy-8, 8,10,12,16-pentamethyl-[ 1-fluoro-2-(2-methyl-oxazol-4-yl)-vinyl]-4,17-dioxa-bicyclo [
14.1.0]heptadecane-5,9-3o dione, (1 S,3 S(Z),75,1 OR,11 S,125,16R)-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]heptadecane-5,9-dione, (1 S,3 S(Z),75, l OR,11 S,125,16R)-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] 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-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, (1 S,3 S(Z),75,1 OR,11 S,125,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3 [ 1-chloro-2-(2-methyl-oxazol-4-yl)-vinyl]-4,17-dioxa-bicyclo [ 14.1.0]
heptadecane-5,9-dione, (1 S,3 S(Z),75,1 OR,11 S,125,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-oxazol-4-yl)-1-chloro-vinyl]-8,8,10,12,16-pentamethyl-4,17-dioxa-I5 bicyclo[14.1.0]heptadecane-5,9-dione, ( 1 S,3 S(Z),75, l OR,11 S,125,16R)-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-[1-2o fluoro-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4-yl)-1-fluoro-vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-oxazol-4-yl)-1-fluoro vinyl]-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione, 25 ( 1 S,3 S(Z),75,1 OR,11 S,125,16R)-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, ( 1 S,3 S(Z),75,1 OR,11 S,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-30 bicyclo[14.1.0]hepta-decane-5,9-dione, ( 1 S,3 S(Z),7 S, l OR,11 S,125,16R)-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]hepta-decane-5,9-dione, (4S,7R,8S,9S,13Z,165(Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[1-chloro-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8 S,9S,13Z,165(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,165(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, ( 1 S,3 S(Z),75,1 OR,11 S,125,16R)-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, ( 1 S,3 S(Z),75,1 OR,11 S,125,16R)-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]hepta-decane-5,9-dione, ( 1 S,3 S(Z),75,1 OR,11 S,125,16R)-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]hepta-decane-5,9-dione, (4S,7R,8S,9S,13Z,165(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,165(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, ( 1 S,3 S(E),75, l OR,115,125,16R)-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, ( 1 S,3 S (E),75,1 OR,11 S,125,16R)-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, ( 1 S,3 S (E),7 S,1 OR,11 S,125,16R)-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,165(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,165(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, (1 S,3 S(E),75, l OR,11 S,125,16R)-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, (1 S,3 S(E),75,1 OR,11 S,125,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-thiazol-4-yl)-vinyl]-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione, ( 1 S,3 S(E),75,1 OR,11 S,125,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-vinyl]-10 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, ( 1 S,3 S (E),7 S,1 OR,11 S,12S,16R)-7,11-Dihydroxy-8, 8,10,12,16-pentamethyl-15 [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, ( 1 S,3 S(E),75,1 OR,11 S,125,16R)-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, 20 (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,8 S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy-25 5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione, (1 S,3 S,7S, l OR,11 S,125,16R)-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, ( 1 S,3 S,7S,1 OR,11 S,125,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-benzothiazol-5-yl)-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [
14.1.0]heptadecane-30 5,9-dione, ( 1 S,3 S,7S,1 OR,11 S,12 S,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, (1 S,3S,7S,1 OR,11 S,125,16R)-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, ( 1 S,3 S,7S,1 OR,11 S,125,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl 1 o benzothiazol-5-yl)-10-ethyl-8, 8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione, ( 1 S,3 S,7 S,1 OR,11 S,12 S,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, 15 (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-20 7-propyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione, ( 1 S,3 S,7S,1 OR,11 S,125,16R)-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, (1 S,3 S,7S,1 OR,11 S,125,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-25 benzothiazol-5-yl)-10-propyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione, ( 1 S,3 S,7S,1 OR,11 S,125,16R)-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, 30 (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,165)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy-7-butyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione, ( 1 S,3 S,7S,1 OR,11 S,125,16R)-7,11-Dihydroxy-10-butyl-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-S-yl)-4,17-dioxa-bicyclo [14.1.0]heptadecane-5,9-dione, ( 1 S,3 S,7S,1 OR,11 S,125,16R)-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-dione, (1 S,3 S,7S,1 OR,11 S,125,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,11-dihydroxy-10-butyl-8, 8,12,16-tetramethyl-4,17-dioxa-bicyclo [
14.1.0]heptadecane-5,9-1 o dione, (4S,7R,8S,9S,13Z,165)-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,165)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5-yl)-7-allyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione, 15 (4S,7R,8S,9S,13Z,165)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy-7-allyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione, (1 S,3 S,7 S, l OR,11 S,125,16R)-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, ( 1 S,3 S,7S,1 OR,11 S,125,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-2o benzothiazol-5-yl)-10-allyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione, ( 1 S,3 S,7S,1 OR,11 S,125,16R)-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, 25 (4S,7R,8S,9S,13Z,165)-4,8-Dihydroxy-7-prop-2-inyl-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,165)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5-yl)-7-prop-2-inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8S,95,13Z,165)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy-3o 7-prop-2-inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione, ( 1 S,3 S,7S,1 OR,11 S,125,16R)-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-dione, ( 1 S,3 S,7 S,1 OR,11 S,125,16R)-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-dione, ( 1 S,3 S,7 S,1 OR,11 S,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-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-io 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, ( 1 S,3 S,7S,1 OR,11 S,125,16R)-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-is 5,9-dione, ( 1 S,3 S,7S,1 OR,11 S,125,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-benzothiazol-5-yl)-10-but-3-enyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [ 14.1.0]heptadecane-5,9-dione, ( 1 S,3 S,7S,1 OR,11 S,125,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,11-2o dihydroxy-10-but-3-enyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-but-3-inyl-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8 S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5-25 yl)-7-but-3-inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy-7-but-3-inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione, ( 1 S,3 S,7S,1 OR,11 S,125,16R)-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-30 5,9-dione, ( 1 S,3 S,7S,1 OR,11 S,125,16R)-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-dione, ( 1 S,3 S,7 S,1 OR,11 S,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-dione, (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-(2-methyl-benzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5-yl)-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione, l0 (1S,3S,7S,lOR,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, (1 S,3 S,7S, l OR,11 S,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-dione, 15 ( 1 S,3 S,7S,1 OR,11 S,125,16R)-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, 20 (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, ( 1 S,3 S,7S,1 OR,11 S,125,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-25 3-(2-methyl-benzoxazol-5-yl)-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione, ( 1 S,3 S,7S,1 OR,11 S,125,16R)-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-dione, ( 1 S, 3 S,7 S, l OR,11 S,125,16R)-3 -(2-Aminomethyl-benzoxazol-5-yl)-7,11-3o 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, ( 1 S,3 S,7S,1 OR,11 S,125,16R)-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, (1 S,3 S,7S,1 OR,11 S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-benzoxazol-5-yl)-10-propyl-8,8,12,16-tetramethyl-4,17-dioxa-to bicyclo[14.1.0]heptadecane-5,9-dione, ( 1 S,3 S,7 S, l OR,11 S,12 S,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-(2-15 methyl-benzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5-yl)-7-butyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy-7-butyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione, 20 ( 1 S,3 S,7S,1 OR,11 S,125,16R)-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-dione, ( 1 S,3 S,7S,1 OR,11 S,125,16R)-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-dione, 25 (1S,3S,7S,lOR,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, 30 (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,8 S,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, ( 1 S,3 S,7S,1 OR,11 S,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, ( 1 S,3 S,7 S,10R,11 S,12S,16R)-7,11-Dihydroxy-3 -(2-hydroxymethyl-benzoxazol-5-yl)-10-allyl-8,8,12,16-tetrainethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione, ( 1 S,3 S,7S,1 OR,11 S,125,16R)-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-inyl-5,5,9,13-tetramethyl-16-to (2-methyl-benzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5-yl)-7-prop-2-inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy-7-prop-2-inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione, 15 ( 1 S,3 S,7S,1 OR,11 S,125,16R)-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-dione, ( 1 S,3 S,7 S,1 OR,11 S,125,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-benzoxazol-5-yl)-10-prop-2-inyl-8,8,12,16-tetramethyl-4,17-dioxa-2o bicyclo[14.1.0]heptadecane-5,9-dione, ( 1 S,3 S,7 S,1 OR,11 S,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,11-dihydroxy-10-prop-2-inyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [ 14.1.0]heptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-but-3-enyl-5,59,13-tetramethyl-16-25 (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, 30 (1S,3S,7S,lOR,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, ( 1 S,3 S,7S,1 OR,11 S,125,16R)-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-dione, (1 S,3 S,7S,1 OR,11 S,125,16R)-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-dione, (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-but-3-inyl-5,5,9,13-tetramethyl-16-(2-methyl-benzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5-l0 yl)-7-but-3-inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy-7-but-3-inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione, (1 S,3 S,7S,1 OR,11 S,125,16R)-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 15 dione, ( 1 S,3 S,7S, l OR,11 S,125,16R)-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-dione, ( 1 S,3 S,7 S, l OR,11 S,12 S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,11-2o dihydroxy-10-but-3-inyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione.
In a compound of general formula (I) according to the invention that contains one of the above-mentioned elements, the hydrogen atoms in the above-mentioned elements are replaced in the positions indicated in formula (I) by radicals Ll-L3, 25 wherein radicals Li-L3 have the above-indicated meanings.
The invention also relates to linkers of general formula IIh RG~ (CH2)o V-(CH2)q FG' IIh, in which RGl can be an O=C=N group or an S=C=N group, and o, V, q and FGl have 30 the meanings that are already mentioned above, as well as linleers of general formula IIIz RG2 (CH2)o V-(CH2)q FGA 1112, in which RG2 can be a Hal-C(=T)-CHR2~ group or a Hal-C(=T)-CHR22-NR~3-C(=T) group or an R26-C(=O)-O-C(=T)-CHR2~ group or an R26-C(=O)-O-C(=T)-CHR22_ NR~3-C(=T) group; R~6 can be Cl-Clp alkyl, aryl, or aralkyl, and o, V, q, T
and FGl have the meanings that are already mentioned above, as well as linkers of general formula III3 RG3 (CH2)o V-(CH2)q FGA
in which 1o RG3 can be an OH group or an NHR24a group or a COOH group, and o, V, q and FG1 have the meanings that are already mentioned above;
but with the proviso that the compound 1-(4-amino-phenyl)-pyrrole-2,5-dione is not included.
The invention also relates to linkers of general formula (IV1):

RG~ (CH2)o /
~(CH2)q W-C(=O)-U-(CH2)~ FG
Is in which RGl is an O=C=N group or an S=C=N group, and o, q, r, W2, Ra7, U and FGl have the meanings that are mentioned in claim 1;
or linkers of general formula (IV2):

RG2 (CH~)o / ' \ 2 '(CH2)q W-C(=O)-U-(CH2)~ FG
in which RG2 is a Hal-C(=T)-CHR22 group or a Hal-C(=T)-CHR22_NR23-C(=T) group or an R26-C(=O)-O-C(=T)-CHR22 group or an R26-C(=O)-O-C(=T)-CHR22-NR23-C(=T) group, wherein R26 is C 1-C l0 alkyl, aryl, or aralkyl, and R22, R23, T, o, q, r, W2, R27, U and FGl have the meanings that are mentioned in claim 1;
or linkers of general formula (IV3):
R~~
RG3 (CH2)o ~(CH2)q W-C(=O)-U-(CH2)~ FG
in which RG3 is an OH group or an NHR24a group or a COOH group, and R24a, o, q, r, W2, R~~, U and FGl have the meanings that are mentioned in claim 1.
to According to the invention, linkers of general formulas IIh, III2 or III3 are preferred, wherein V represents a bond or an aryl radical, o is equal to zero, and T is an oxygen atom.
In addition, linkers of general formulas IIh, III2 or III3 according to the invention are preferred, in which V represents a bond or an aryl radical or a group N R24b-C(=~)-~_(C H2)S
15 Q ~ Q represents a bond or a group -O-C(=O)-N R24~-C' and o is 0 to 4. Especially preferred from the above are those linkers in which V represents a bond or a group .NR24b-C(=O)-0-(CH2)S
Q represents a bond or a group -O-C(=O)-N R24~--o is equal to 0, 2 or 3; s is equal to 1; and T is an 20 oxygen atom.
In addition, preferred according to the invention are linkers of general formulas IV', IV2 or IV3, in which o is zero to four and q is zero to three. Especially preferred from the above are those linkers in which o is 0, 2 or 3; Wl is an oxygen atom; q is equal to 0; R22 is hydrogen, CI-C3 alkyl or aralkyl; R23 is hydrogen or C~-C3 alkyl; R24a is hydrogen or CI-C3 alkyl; R2' is fluorine, chlorine, CN, NOa, CO~RaB or OR~'8; RZ8 is hydrogen or C~-CS alkyl; and U is oxygen, CHRa2 or CHR~'Z-NR23-C(=O).
Additionally, the invention relates to methods to react a linker of general formula IIIi or IV1 with a compound of general formula I, in which the condition that at least one group Ll, L~ or L4 represent a linker need not be met, and in which Ll andlor L2 andlor L4 have the meaning of a hydrogen atom, and free hydroxyl groups and/or amino groups that are not required for the reaction optionally are protected, to react a linker of general formula III2 or IVZ with a compound of general to formula I, in which the condition that at least one group Ll, L~ or L4 represent a linker need not be met, and L1 andlor L2 andlor L4 have the meaning of a hydrogen atom, and free hydroxyl groups and/or amino groups that are not required for the reaction are optionally protected, or to react a linker of general formula III3 or IV3 with a compound of general 15 formula I, in which the condition that at least one group Ll, L~ or L4 represent a linker need not be met, and L1 and/or L2 and/or L4 have the meaning of a C(=O)Hal group or a C(=S)Hal group, and free hydroxyl groups and/or amino groups that are not required for the reaction are optionally protected.
The invention also relates to the use of a compound of general formula I, 2o wherein the substituents have the above-mentioned meanings, but the condition that at least one substituent LI, Lz or L4 represents a linker of general formula III
or IV need not be met, and at least one substituent Li, L2 or L4 represents hydrogen, a group C(=O)Cl, or a group C(S)Cl , in a method as described above.
The invention also relates to the use of a compound of general formula I, 25 wherein the substituents have the above-mentioned meanings, but the condition that at least one substituent Ll, LZ or L4 represent a linker of general formula III
or IV need not be met, and at least one substituent Ll, L2 or L4 represents hydrogen, a group C(=O)Cl, or a group C(S)Cl, for the production of an effector recognition unit conjugate as described above.
3o The invention also relates to the use of a linker of general formula IIh, III2, III3, IV1, IVZ or IV3 for the production of an effector conjugate, as described above.

The invention also relates to the use of a linker of general formula III1, III2, III3, IV1, IV2 or IV3 for the production of an effector recognition unit conjugate as described above.
The invention also relates to the use of a recognition unit, as described above, in a process according to the invention for the production of an effector recognition unit conjugate, as described above.
The invention also relates to the effector recognition unit conjugates according to the invention for use as a medicament or for the production of a medicament or a pharmaceutical composition.
to The invention relates finally to the use of the effector recognition unit conjugates according to the invention for the production of medicaments for the treatment of diseases that are associated with proliferative processes, such as tumors, inflammatory andlor neurodegenerative diseases, multiple sclerosis, Alzheimer's disease, or for the treatment of angiogenesis-associated diseases, such as tumor 15 growth, rheumatoid arthritis or diseases of the ocular fundus.

Examples of the Synthesis of Linkers (L) Example L 1 (S) 2-[(3-Methyltrisulfanyl-propionyl)-methyl-amino]-propanoic acid Example L 1 a (S) 2-[(3-Acetylsulfanyl-propionyl)-methyl-amino]-propanoic acid ethyl ester The solution of 15 g (89.5 mmol) of N-methylalanine ethyl ester-hydrochloride in X50 ml of anhydrous tetrahydrofuran is mixed at 23°C with 4.1 g of an to approximately 60% sodium hydride dispersion and, after 3 hours, with 23.5 g of 3-acetylsulfanyl-propanoic acid chloride. It is allowed to react for two days, mixed with saturated sodium bicarbonate solution, and extracted several times with ethyl acetate.
The combined organic extracts are washed with saturated sodium chloride solution, dried over sodium sulfate, and the residue that is obtained after filtration and removal 15 of the solvent is purified by chromatography on fine silica gel. 17.6 g (67.3 mmol, 75%) of the title compound is isolated as a colorless oil.
Example Llb (S) 2-[(3-Mercapto-propionyl)-methyl-amino]-propanoic acid 2o The solution of 17.6 g (67.3 mmol) of the compound prepared according to Example Lla in 150 ml of methanol is mixed at 23°C with 44 ml of a SM
sodium hydroxide solution, and it is stirred for 5 hours. By adding 4N hydrochloric acid, a pH
of 2 is set, and it is extracted with dichloromethane. The combined organic extracts are washed with saturated sodium chloride solution and dried over sodium sulfate.
25 The residue that is obtained after filtration and removal of the solvent (13.0 g, maximum 67.3 mmol) is further reacted without purification.
Example Llc (S) 2-[(3-Mercapto-propionyl)-methyl-amino]-propanoic acid methyl ester 3o The solution of 4.53 g (maximum 23.7 mol) of the crude product, prepared according to Example Llb, in 135 ml of diethyl ether is esterified at 0°C with an ethereal solution of diazomethane. After removal of the solvent, 4.59 g (22.4 mmol, 94%) of the title compound is isolated as a pale yellow oil, which is further reacted without purification.
Example Lld (S) 2-[(3-Methyltrisulfanyl-propionyl)-methyl-amino]-propanoic acid methyl ester The solution of 14 g (68.2 mmol) of the compound, prepared according to Example Llc, in 180 ml of trichloromethane is added to the solution of 21 g of methyldisulfanyl-isoindole-1,3-dione in 420 ml of trichloromethane, and it is stirred for 16 hours at 23°C. It is concentrated by evaporation, dissolved in dichloromethane, 1o and stirred for 0.5 hour. Solid is filtered off, the filtrate is concentrated by evaporation, and the residue is purified by chromatography on fine silica gel. 16.2 g (57.2 mmol, 84%) of the title compound is isolated as a colorless oil.
Example Ll (S) 2-[(3-Methyltrisulfanyl-propionyl)-methyl-amino]-propanoic acid The solution of 10 g (35.3 mmol) of the compound, prepared according to Example Lld, in 20 ml of ethanol is mixed with 1 1 of phosphate puffer with a pH of 7, pig liver esterase, and it is incubated at 27°C for 46 hours. By adding a 4N
hydrochloric acid, the pH is adjusted to 1, it is extracted with dichloromethane, dried over sodium sulfate, and after filtration and removal of the solvent, 8.3 g (30.8 mmol, 87%) of the title compound is isolated as a colorless oil, which is reacted without further purification.
1H NMR (CDC13): 8 = 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.
Example L2 [(3-Methyltrisulfanyl-propionyl)-methyl-amino]-acetic acid Example L2a 2-[(3-Acetylsulfanyl-propionyl)-methyl-amino]-acetic acid ethyl ester 7.13 g (46.4 mmol) of N-methylglycine ethyl ester-hydrochloride is reacted analogously to Example Lla, and 6.9 g (27.9 mmol, 60%) of the title compound is isolated as a colorless oil.

Example L2b [(3-Mercapto-propionyl)-methyl-amino]-acetic acid 7.6 g (30.7 mmol) of the compound that is prepared according to Example L2a is reacted analogously to Example Llb, and 4.92 g (27.8 mmol, 90%) of the title compound is isolated as a colorless oil.
Example L2c lo [(3-Mercapto-propionyl)-methyl-amino]-acetic acid methyl ester 4.92 g (27.8 mmol) of the compound that is prepared according to Example L2b is reacted analogously to Example Llc, and 5.01 g (26.2 mmol, 94%) of the title compound is isolated as a colorless oil.
15 Example L2d [(3-Methyltrisulfanyl-propionyl)-methyl-amino]-acetic acid methyl ester 2.00 g ( 10.5 mmol) of the compound that is prepared according to Example L2c is reacted analogously to Example Lld, and 2.33 g (8.65 mmol, 82%) of the title compound is isolated as a colorless oil.
Example L2 [(3-Methyltrisulfanyl-propionyl)-methyl-amino]-acetic acid 2.00 g (7.83 mmol) of the compound that is prepared according to Example L2d is reacted analogously to Example L1, and 0.64 g (2.51 mmol, 32%) of the title compound is isolated as a colorless oil.
1H-NMR (CDCl3): 8 = 2.41+2.56 (3H), 2.61-3.27 (7H), 3.98 (2H), 4.38 (1H) ppm.
Example L3 (S) 2-[(3-Methyltrisulfanyl-propionyl)-methyl-amino]-3-phenyl-propionic acid Example L3a (S) 2-[(3-Acetylsulfanyl-propionyl)-methyl-amino]-3-phenyl-propanoic acid ethyl ester 7.73 g (31.7 mmol) of N-methylphenylalanine ethyl ester-hydrochloride is reacted analogously to Example Lla, and 2.3 g (6.82 mmol, 22%) of the title compound is isolated as a colorless oil.
Example L3b (S) 2-[(3-Mercapto-propionyl)-methyl-amino]-3-phenyl-propanoic acid l0 1.09 g (3.23 mmol) of the compound that is prepared according to Example L3a is reacted analogously to Example Llb, and 0.744 g (2.78 mmol, 86%) of the title compound is isolated as a colorless oil.
Example L3c 15 (S) 2-[(3-Mercapto-propionyl)-methyl-amino]-3-phenyl-propanoic acid methyl ester 0.74 g (2.77 mmol) of the compound that is prepared according to Example L3b is reacted analogously to Example Llc, and 0.77 g (2.74 mmol, 99%) of the title compound is isolated as a colorless oil.
2o Example L3d (S) 2-[(3-Methyltrisulfanyl-propionyl)-methyl-amino]-3-phenyl-propanoic acid methyl ester 0.77 g (2.74 mmol) of the compound that is prepaxed according to Example L3c is reacted analogously to Example Lld, and 0.72 g (2.00 mmol, 73%) of the title 25 compound is isolated as a colorless oil.
Example L3 (S) 2-[(3-Methyltrisulfanyl-propionyl)-methyl-amino]-3-phenyl-propanoic acid 0.72 g (2.00 mmol) of the compound that is prepared according to Example 3o L3d is reacted analogously to Example L1, and 0.49 g (1.42 mmol, 71%) of the title compound is isolated as a colorless oil.
Example L4 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-butanoic acid 20.0 g (193.9 mmol) of 4-aminobutyric acid is mixed with 19 g of malefic acid anhydride, 290 ml of acetic acid, and it is heated for 4 hours in an oil bath at 130°C. It is azeotropically concentrated by evaporation with repeated addition of toluene, the residue is dissolved in dichloromethane and purified by chromatography on fine silica gel. 17.1 g (93.4 mmol, 48%) of the title compound is isolated as a crystalline solid.
1H-NMR (CDC13): 8 = 1.93 (2H), 2.38 (2H), 3.60 (2H), 6.71 (2H) ppm.
Example L4a to 1-(3-Isocyanato-propyl)-pyrrole-2,5-dione 5.0 g (27.3 mmol) of the compound that is prepared according to Example L4 is dissolved in 90 ml of tetrahydrofuran, mixed with 8 ml of triethylamine and 6.17 ml of phosphoric acid diphenylester azide, and it is stirred for 1.5 hours at 23°C. Then, it is mixed with 110 ml of toluene, the tetrahydrofuran is distilled off, and it is heated for 2 15 hours to 70°C. The crude product is purified by chromatography on fme silica gel.
1.77 g (9.82 mmol, 36%) of the title compound is isolated.
Example LS
20 6-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoic acid 100 g (762 mmol) of 6-aminocaproic acid is reacted analogously to Example L5, and 93.8 g (444 mmol, 58%) of the title compound is isolated as a crystalline solid.
1H-NMR (CDC13): b =1.34 (2H), 1.55-1.70 (4H), 2.34 (2H), 3.51 (2H), 6.69 (2H) ppm.
Example LSa 1-(5-Isocyanato-pentyl)-pyrrole-2,5-dione 10.0 g (47.3 mmol) of the compound that is prepared according to Example LS
is reacted analogously to Example L4a, and 3.19 g (15.3 mmol, 32%) of the title 3o compound is isolated as a colorless oil.
Example L6 11-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-undecanoic acid g (49.7 mmol) of 11-aminoundecanoic acid is reacted analogously to Example L5, and 6.29 g (22.4 mmol, 45%) of the title compound is isolated as a crystalline solid.
1H-NMR (CDC13): 8 =1.19-1.36 (12H), 1.51-1.67 (4H), 2.34 (2H), 3.49 (2H), 5 6.68 (2H) ppm.
Example L6a 1-(10-Isocyanato-decyl)-pyrrole-2,5-dione 5.28 g (18.8 mmol) of the compound that is prepared according to Example L6 to is reacted analogously to Example L4a, and 3.37 g (12.1 mmol, 64%) of the title compound is isolated as a colorless oil.
Example L7 1-(4-Amino-phenyl)-pyrrole-2,5-dione IS The solution of 21.6 g (200 mznol) of 1,4-phenylenediamine in 200 ml of tetrahydrofuran is mixed over 1.5 hours with the solution of 19.6 g of malefic acid anhydride, and it is stirred for 22 hours at 23°C. It is filtered, rewashed with tetrahydrofuran, and the filtrate is dried. 37.1 g (197 mmol, 98%) of the title compound is isolated as a crystalline solid.
1H-NMR (d6-DMSO): 8 = 6.28 (1H), 6.48 (1H), 6.53 (2H), 7.30 (2H), 7.50-9.00 (2H) ppm.
Example L8 1-(4-Hydroxy-phenyl)-pyrrole-2,5-dione The suspension that consists of 5.0 g (45.8 mmol) of 4-aminophenol, 4.49 g of malefic acid anhydride and 40 ml of acetic acid is refluxed for 3 hours. It is concentrated by evaporation, residual acetic acid is removed azeotropically by repeated distillation with acetic acid, and the residue is purified by chromatography on fine silica gel. 2.83 g (15.0 mmol, 33%) of the title compound is isolated.
1H-NMR (d6-DMSO): b = 6.83 (2H), 7.09 (2H), 7.13 (2H), 9.71 (1H) ppm.
Example L9 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-butanoic acid 4-hydroxymethyl-2-nitro-phenyl ester The solution of 5.0 g (29.6 mmol) of 4-hydroxymethyl-2-nitro-phenol in 250 ml of dichloromethane is mixed with 6.1 g of N,N'-dicyclohexylcarbodiimide and 2.4 ml of pyridine, and the solution of 5.5 g of the compound, prepared according to Example L4, in 250 ml of dichloromethane, is added dropwise within 15 minutes.
It is stirred for one more hour at 23°C, filtered, the filtrate is concentrated by evaporation and purified by chromatography on fine silica gel. 1.73 g (5.2 mmol, 18%) of the title compound is isolated.
io 1H NMR (CDC13): 8 = 2.07 (3H), 2.67 (2H), 3.67 (2H), 4.79 (2H), 6.72 (2H), 7.28 (1H), 7.66 (1H), 8.10 (1H) ppm.
Example L10 6-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoic acid 4-hydroxymethyl-2-nitro-phenyl is ester Analogously to Example L9, 5.0 g (29.6 mmol) of 4-hydroxymethyl-2-nitro-phenol is reacted with 6.34 g of the compound that is prepared according to Example L5, and after working-up and purification, 3.78 g (10.4 mmol, 35%) of the title compound is isolated.
20 1H-NMR (CDC13): 8 =1.42 (2H), 1.66 (2H), 1.88 (2H), 2.64 (2H), 3.55 (2H), 4.78 (2H), 6.69 (2H), 7.21 (1H), 7.64 (1H), 8.09 (1H) ppm.
Example L11 11-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-undecanoic acid 4-hydroxymethyl-2-nitro-25 phenyl ester Analogously to Example L9, 5.0 g (29.6 mmol) of 4-hydroxymethyl-2-nitro-phenol is reacted with 8.44 g of the compound that is prepared according to Example L6, and after working-up and purification, 3.78 g (10.4 mmol, 35%) of the title compound is isolated.
30 1H-NMR (CDCl3): b = 1.21-1.63 (14H), 1.76 (2H), 1.99 (1H), 2.63 (2H), 3.51 (2H), 4.78 (2H), 6.68 (2H), 7.21 (1H), 7.65 (1H), 8.10 (1H) ppm.
Example L12 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-butanoic acid 4-hydroxymethyl-phenyl ester 5.5 g (23,1 mmol) 4-tert-Butyldimethylsilanyloxymethyl-phenol, 20 mg N,N-Dimethyl-4-aminopyridine and 4.23 g (23,1 mmol) of the compound prepared according to Example L4 are dissolved in 92 ml of dichloromethane and cooled to 0°C. 4.77 g (23.1 mmol) N,N'-Dicyclohexylcarbodiimide in 24 ml dichloromethane are added dropwise to the cooled solution over a period of 15 min. The mixture is stirred for 16 hours at 23°C, filtered, the filtrate is concentrated and purified by chromatography on fme silica gel. 7.18 g (17.8 mmol, 77%) 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-butanoic acid-4-tent-butyldimethylsilanyloxymethyl-phenyl ester are isolated. 1.42 g thereof are dissolved in 63 ml THF and 7 ml water, and 0.67g (3.52 mmol) p-toluenesulfonic acid are added at room temperature. After 16 hours, a saturated sodium bicarbonate solution is added and the mixture is extracted several times with ethyl acetate. The combined organic layers are washed with a satwated solution of sodium chloride, dried over sodium sulfate and purified by chromatography on fine silica gel. 0.43 g (1.5 mmol, 42%) of the title compound are isolated.
1H-NMR (CDCl3): b = 1.71 (1H), 2.04 (2H), 2.58 (2H), 3.67 (2H), 4.68 (2H), 6.71 (2H), 7.09 (2H), 7.38 (2H) ppm.
Example L13 6-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoic acid 4-hydroxymethyl-phenyl ester Analogously to Example L12, 4.02 g (13.8 mmol) 4-tert-butyldimethylsilanyloxymethyl- phenol are reacted with 3.56 g (13.8 mmol) of the compound prepared according to Example L5. After working-up, purification and analogous treatment with p-toluenesulfonic acid, 3,19 g (10.1 mmol, 60%) of the title compound are isolated.
1H-NMR (CDC13): b = 1.42 (2H), 1.59-1.83 (5H), 2.55 (2H), 3.55 (2H), 4.68 (2H), 6.69 (2H), 7.06 (2H), 7.3 8 (2H) ppm.
Example L 14 11-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-undecanoic acid 4-hydroxymethyl-phenyl ester Analogously to Example L12, 5.41 g (22.7 mmol) 4-tert-butyldimethylsilanyloxymethyl- phenol are reacted with 6.39 g (22.7 mmol) of the compound prepared according to Example L6. After working-up, purification and analogous treatment with p-toluenesulfonic acid, 5.91 g (15.3 mmol, 67%) of the title compound are isolated.
1H-NMR (CDC13): 8 = 1.24-1.43 (12H), 1.57 (3H), 1.74 (2H), 2.55 (2H), 3.50 (2H), 5 4.69 (2H), 6.68 (2H), 7.06 (2H), 7.38 (2H) ppm.
Example L15 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-butanoic acid 4-hydroxymethyl-2-chloro-phenyl ester to Analogously to Example L9, 5.0 g (29.6 mmol) of 4-hydroxymethyl-2-chloro-phenol are reacted with 5.42 g of the compound prepared according to Example L4.
After working-up and purification, 8.49 g (26.2 mmol, 89%) of the title compound are isolated.
1H-NMR (CDCl3): b = 2.07 (3H), 2.64 (2H), 3.67 (2H), 4.67 (2H), 6.72 (2H), 7.14 15 (1H), 7.27 (1H), 7.46 (1H) ppm.
Example L 16 6-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoic acid 4-hydroxymethyl-2-chloro-phenyl ester 2o Analogously to Example L9, 5.0 g (29.6 mmol) of 4-hydroxymethyl-2-chloro-phenol are reacted with 6.24 g of the compound prepared according to Example L5.
After working-up and purification, 5.11 g (14.5 mmol, 49%) of the title compound are isolated.
1H-NMR (CDCl3): 8 = 1.43 (2H), 1.66 (2H), 1.81 (3H), 2.61 (2H), 3.55 (2H), 4.67 25 (2H), 6.69 (2H), 7.10 ( 1 H), 7.26 ( 1 H), 7.46 ( 1 H) ppm:
Example L17 11-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-undecanoic acid 4-hydroxymethyl-2-chloro-phenyl ester 3o Analogously to Example L9, 4.61 g (29 mmol) 4-hydroxymethyl-2-chloro-phenol are reacted with 8.17 g of the compound prepared according to Example L6. After working-up and purification, 4.61 g (10.9 mmol, 38%) of the title compound are isolated.

sl 1H-NMR (CDC13): 8= 1.18-1.84 (17H), 2.61 (2H), 3.51 (2H), 4.67 (2H), 6.68 (2H), 7.10 (1H), 7.27 (1H), 7.46 (1H) ppm.
Example L18 s 1-(6-Hydroxy-hexyl)-pyrrol-2,5-dione 26 ml of a 1,OM solution of borane-tetrahydrofurane-complex in tetrahydrofurane is added to a solution of 5.0 g (23.7 mmol) of the acid prepared according to Example LS
in 50 ml of anhydrous tetrahydrofurane and the mixture is stirred for 3 hours at 23°C.
The mixture is poured into a saturated solution of sodium bicarbonate, extracted to several times with ethyl acetate, and the combined organic extracts are dried over sodium sulfate. After filtration and removal of the solvent, the residue is purified by chromatography. 2.53 g (12.8 mmol, 54%) of the title compound are isolated.
1H-NMR (CDC13): 8=1.24-1.65 (9H), 3.52 (2H), 3.63 (2H), 6.68 (2H) ppm.
is Examples of the Synthesis of Effector-Linker Conjugates (EL) Example EL1 (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 Example EL 1 a (4S,7R,8S,9S,13Z,16S)-7-Allyl-8-(tent-butyl-dimethyl-silanyloxy)-4-hydroxy l0 5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6 dione The solution of 6.0 g (7.93 mmol) of (4S,7R,8S,9S,13Z,16S)-7-allyl-4,8-bis(tart-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione, which was produced analogously to the 15 process that is described in WO 00/66589, in 186 ml of anhydrous dichloromethane is mixed at 0°C with 26.4 ml of a 20% solution of trifluoroacetic acid in dichloromethane, and it is stirred for 6 hours at 0°C. It is poured into saturated sodium bicarbonate solution, extracted with dichloromethane, the combined organic extracts are washed with water and dried over magnesium sulfate. The residue that is obtained 2o after filtration and removal of the solvent is purified by chromatography on fine silica gel. 3.32 g (5.17 mmol, 65%) of the title compound is isolated as a colorless solid.
1H-NMR (CDC13): 8 = 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 (SH), 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 25 (1H), 7.34 (1H), 7.78 (1H), 7.95 (1H) ppm.
Example ELlb (4S,7R,8S,9S,13Z,16S)-3-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-propyl]-carbamic acid-7-allyl-8-tart-butyl-dimethylsilyloxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-30 5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yl ester 50 mg (78 ~mol) of the compound that is prepared according to Example ELla is dissolved in a mixture of 1.5 ml of trichloromethane and 1.5 ml of dimethylformamide, mixed with 144 mg of the linker that is prepared according to Example L4a, 79 mg of copper(I) chloride, and it is heated for 18 hours to 70°C. The crude mixture is purified by chromatography on thin-layer plates, and 51 mg (62 ~mol, 80%) of the title compound is isolated as a colorless oil.
Example EL1 (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-ylester The solution of 41 mg (50 ~,mol) of the compound, prepared according to to Example lb, in a mixture of 0.8 ml of tetrahydrofuran and 0.8 ml of acetonitrile is mixed with 310 ~1 of hexafluorosilicic acid, 310 ~1 of hydrogen fluoride-pyridine complex, and it is stirred for 23 hours at 23°C. It is poured into a 5%
sodium hydroxide solution, extracted with ethyl acetate, the combined organic extracts are washed with a saturated sodium chloride solution and dried over sodium sulfate. The 15 residue that is obtained after filtration and removal of the solvent is purified by chromatography on thin-layer plates, and 26 mg (36.7 ~.mol, 73°/~) of the title compound is isolated as a colorless foam.
1H-NMR (CDCl3): 8 = 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 20 (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.
Example EL2 (1 S,3 S,7S, l OR,11 S,125,16R)-[3-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-propyl]-25 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 ( 1 R, 3 S,7 S,1 OR,11 S,12 S,16 S)-[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) 3o The solution of 44 mg (62.2 ~.mol) of the compound, prepared according to Example 1, in 2.0 ml of dichloromethane is cooled to -50°C and mixed in portions over a period of 1.5 hours with a total of 1.7 ml of an approximately 0.1 M
solution of dimethyl dioxiran in acetone. It is poured into a saturated sodium thiosulfate solution, extracted with dichloromethane, and the combined organic extracts are dried over sodium sulfate. The residue that is obtained after filtration and removal of the solvent is purified by chromatography on thin-layer plates, and 22.7 mg (31.4 ~,mol, 50%) of title compound A as well as 7.6 mg (10.5 pmol, 17%) of title compound B are isolated in each case as a colorless foam.
1H-NMR (CDCl3) of A: 8 =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.
l0 1H-NMR (CDCl3) of B: 8 =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.
15 Example EL3 (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 2o Example EL3a (4S,7R,8S,9S,13Z,16S)-[5-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-pentyl]-carbamic acid-7-allyl-8-tent-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 pmol) of the compound that is prepared according to Example ELla 25 is reacted analogously to Example ELlb with the linker that is produced according to Example LSa, and after purification, 39 mg (45.9 ~mol, 59%) of the title compound is isolated as a colorless oil.
Example EL3 30 (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 55.
84 mg (98.8 ~.mol) of the compound that is prepared according to Example EL3a is reacted analogously to Example EL1, and after purification, 43 mg (58.4 ~,mol, 59%) of the title compound is isolated as a colorless foam.
1H-NMR (CDCl3): b = 0.89 (3H), 0.96 (3H), 0.85-1.97 (17H), 1.12 (3H), 2.16-3.01 (lOH), 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 ( 1 H) ppm.
Example EL4 to (1S,3S,7S,lOR,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 (1 R,3 S,7S, l OR,11 S,125,16S)-[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)-5,9-15 dioxo-4,17-dioxabicyclo[14.1.0]heptadec-7-yl ester (B) 26 mg (35.3 ~,mol) of the compound that is prepared according to Example EL3 is reacted analogously to Example EL2, and after purification, 9.1 mg (12.1 ~,mol, 34%) of title compound A as well as 3.0 mg (4.0 ~.mol, 11%) of title compound B are isolated in each case as a colorless foam.
20 1H-NMR (CDC13) of A: 8 = 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 ( 1 H) ppm.
1H-NMR (CDC13) of B: 8 = 0.78-2.74 (23H), 1.01 (3H), 1.03 (3H), 1.33 (3H), 25 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.
Example ELS
30 (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 Example ELSa (4S,7R,8S,9S,13Z,16S)-[10-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-decyl]-carbamic acid-7-allyl-8-tent-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 ~.mol) of the compound that is prepared according to Example ELla is reacted analogously to Example ELlb with the linker that is produced according to Example L6a, and after purification, 56 mg (60.8 ~,mol, 78%) of the title compound is isolated as a colorless oil.
1o Example ELS
(4S,7R,8S,9S,13Z,16S)-[10-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-decylJ-carbamic acid-7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-ylester 20 mg (21.7 ~.mol) of the compound that is prepared according to Example 15 ELSa is reacted analogously to Example EL1, and after purification, 10 mg (12.4 ~.mol, 57%) of the title compound is isolated as a colorless foam.
1H-NMR (CDC13): ~ = 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 2o (2H), 7.37 (1H), 7.77 (1H), 7.90+7.97 (1H) ppm.
Example EL6 ( 1 S,3 S,7 S,1 OR,11 S,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-5-25 yl)-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-7-yl ester (A) and ( 1 R,3 S,7S, l OR,11 S,125,16S)-[ 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.l.OJheptadec-7-yl ester (B) 18 mg (22 ~mol) of the compound that is prepared according to Example ELS
3o is reacted analogously to Example EL2, and after purification, 9.2 mg (11.2 ~.mol, 51 %) of title compound A as well as 3.2 mg (3.9 ~mol, 18%) of title compound B are isolated in each case as a colorless foam.

1H-NMR (CDC13) of A: b = 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 (CDC13) of B: 8 = 0.80-1.64 (21H), 1.01 (3H), 1.03 (3H), 1.25 (3H), 1.33 (3H), 1.79-2.25 (SH), 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 ( 1 H) ppm.
Example EL7 (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 Example EL7a (4S,7R,8S,9S,13Z,16S)-7-Allyl-4-(tent-butyl-dimethyl-silanyloxy)-8-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione The solution of 5.3 g (7.01 mmol) of (4S,7R,8S,9S,13Z,16S)-7-allyl-4,8-bis(tart-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione, which was produced analogously to the process described in WO 00/66589, in a mixture of 85 ml of tetrahydrofuran and 85 ml of acetonitrile, is mixed with 31.7 ml of hexafluorosilicic acid, cooled to 0°C, 8.1 ml of trifluoroacetic acid is added dropwise, and it is stirred for 20 hours at 0°C. It is poured into water, neutralized by adding a saturated sodium bicarbonate solution and extracted several times with ethyl acetate. The combined organic extracts are washed with saturated sodium chloride solution, dried over sodium sulfate, and the residue that is obtained after filtration and removal of the solvent is purified by chromatography on 3o fine silica gel. 2.82 g (4.39 mmol, 63%) of the title compound is isolated as a colorless solid.
1H-NMR (CDCl3): 8 = -0.09 (3H), 0.08 (3H), 0.84 (9H), 1.08 (3H), 1.10 (3H), 1.12 (3H), 1.21-1.86 (SH), 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.
Example EL7b (4S,7R,8S,9S,13Z,16S)-[3-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-propyl]-carbamic acid-7-allyl-4-tent-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 p.mol) of the compound that is prepared according to Example EL7a is reacted analogously to Example ELlb with the linker that is produced to according to Example L4a, and after purification, 121 mg (147 ~.mol, 94%) of the title compound is isolated as a colorless oil.
Example EL7 (4S,7R,8S,9S,13Z,16S)-[3-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-propyl]-carbamic acid-15 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 ~,mol) of the compound that is prepared according to Example EL7b is reacted analogously to Example ELl, and after purification, 17 mg (24 ~,mol, 43%) of the title compound is isolated as a colorless foam.
20 1H-NMR (CDCl3): 8 = 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.
Example EL8 ( 1 S,3 S,7 S,1 OR,11 S,12S,16R)-[3-(2,5-Dioxo-2,S-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,lOR,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 ~,mol) of the compound that is prepared according to Example EL7 is reacted analogously to Example EL2, and after purification, 18 mg (24.9 pmol, 61%) of title compound A as well as 3.0 mg (4.1 ~mol, 10%) of title compound B
are isolated in each case as a colorless foam.
1H NMR (CDCl3) of A: b = 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 ( 1 H), 4.10 ( 1 H), 4.95-5 .02 (2H), 5 .17 (2H), 5.77 ( 1 H), 6.19 ( 1 H), 6.70 (2H), 7.3 8 ( 1 H), 7.82 (1H), 7.97 (1H) ppm.
1H NMR (CDCl3) of B: b = 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 (iH), 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.
Example EL9 (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 Example EL9a (4S,7R,8S,9S,13Z,16S)-[5-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-pentyl]-carbamic acid-7-allyl-4-tart-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 ~mol) of the compound that is prepared according to Example EL7a is reacted analogously to Example ELlb with the linker that is produced according to Example LSa, and after purification, (65.9 p,mol, 42%) of the title compound is isolated as a colorless oil.
Example EL9 (4S,7R,8S,9S,13Z,16S)-[5-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-pentyl]-carbamic acid-7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-3o oxacyclohexadec-13-en-8-yl ester 56 mg (65.9 p.mol) of the compound that is prepared according to Example EL7b is reacted analogously to Example ELl, and after purification, 24.7 mg (33.6 p.mol, 51 %) of the title compound is isolated as a colorless foam.

1H-NMR (CDCl3): 8 = 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.
Example EL10 ( 1 S,3 S,7S,1 OR,11 S,125,16R)-[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 (1 S,3 S,7S,1 OR,11 S,12S,16R)-[5-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-pentyl]-carbamic 1o acid-10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxabicyclo[14.1.0]hepta-dec-11-yl ester (B) 24.7 mg (33.6 ~,mol) of the compound that is prepared according to Example EL9 is reacted analogously to Example EL2, and after purification, 16.7 mg (22.2 ~.mol, 66%) of title compound A as well as 2.0 mg (2.7 p.mol, 8%) of title compound B
15 are isolated in each case as a colorless foam.
1H-NMR (CDC13) of A: 6 = 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.
20 1H-NMR (CDC13) of B: 8 = 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.
Example EL11 25 (1S,3S(E),7S,lOR,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 ~mol) of (1S,3S(E),7S,lOR,11S,12S,16R)-7,11-dihydroxy-30 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 reacted analogously to Example ELlb with the linker that is produced according to Example L4a, and after purification, 7 mg (8.06 ~mol, 41%) of the title compound is isolated as a colorless oil.

1H-NMR (CDC13): b = 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 (SH), 6.52 (1H), 6.69 (2H), 6.71 (2H), 7.02 (1H) ppm.
Example EL12 (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 to Example ELl2a (4S,7R,8S,9S,13Z,16S)-Chloroformic acid-7-allyl-8-(test-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-en-4-yl ester The solution of 1.0 g (1.56 mmol) of the compound, prepared according to 15 Example ELla, in 20 ml of dichloromethane is mixed at 0°C with the solution of 285 mg of triphosgene in 6 ml of dichloromethane, 160 ~1 of pyridine, and it is stirred for 2.5 hours at 23°C. It is concentrated by evaporation, the residue is dissolved in ethyl acetate, washed with water and saturated sodium chloride solution, and dried over magnesium sulfate. The residue that is obtained after filtration and removal of the 2o solvent is purified by chromatography on fine silica gel. 1.08 g (1.53 mmol, 98%) of the title compound is isolated.
Example ELl2b (4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-8-(tart-butyl-dimethyl-silanyloxy)-25 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 The solution of 267 mg (370 ~mol) of the compound, prepared according to Example ELl2a, in 16 ml of ethyl acetate, is mixed with 51 ~.1 of triethylamine, 700 mg of the compound that is prepared according to Example L8, and it is stirred for 16 3o hours at 23°C. It is poured into water, extracted several times with ethyl acetate, the combined organic extracts are washed with saturated sodium chloride solution and dried over magnesium sulfate. The residue that is obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel. 188 rng (219 ~mol, 59%) of the title compound is isolated.
Example EL12 (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-I3-en-4-yl ester 4-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-phenyl ester Analogously to Example EL1, 248 mg (289 ~mol) of the compound that is prepared according to Example EL 12a is reacted, and after working-up and l0 purification, 149 mg (201 ~,mol, 69%) of the title compound is isolated.
1H-NMR (CDCl3): b =1.08 (3H), 1.14 (3H), 1.26 (3H), 1.04-1.90 (8H), 2.24-2.57 (6H), 2.68-2.99 (3H), 2.81 (3H), 3.45 (1H), 3.72 (1H), 5.02 (1H), 5.06 (1H), 5.17 ( 1 H), 5.65 ( 1 H), 5.74 ( 1 H), S .98 ( 1 H), 6.79 (2H), 6.88 (2H), 7.21 (2H), 7.3 3 ( 1 H), 7.64 (1H), 7.97 (1H) ppm.
Example EL13 (1S,3S,7S,lOR,11S,12S,16R)-Carbonic acid-10-allyl-11-hydroxy-8,8,12,I6-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 2o Analogously to Example EL2, 144 mg (194 ~,mol) of the compound that is prepared according to Example EL12 is reacted, and after working-up and purification, 89 mg (117 ~,mol, 60%) of the title compound is isolated.
1H-NMR (CDCl3): & =1.10 (3H), 1.14 (3H), 1.27 (3H), 1.32 (3H), 1.19-1.85 (7H), 2.08-2.89 (8H), 2.81 (3H), 3.50 (1H), 3.70 (1H), 5.02 (1H), 5.07 (1H), 5.58 (1H), 2s 5.72 (1H), 6.10 (1H), 6.81 (2H), 6.88 (2H), 7.21 (2H), 7.31 (iH), 7.68 (1H), 7.93 (1H) ppm.
Example EL14 (4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-30 methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yl ester 4-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-phenyl ester Example EL 14a (4S,7R,8S,9S,13Z,16S)-Chloroformic acid-7-allyl-4-(tart-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-S-yI)-2,6-dioxo-oxacyclohexadec-en-8-yl ester Analogously to Example ELl2a, 1.0 g (1.56 mmol) of the compound that is prepared according to Example EL7a is xeacted, and 1.05 g (1.49 mmol, 96%) of the title compound is isolated.
Example ELl4b (4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-4-(tart-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-S-yl)-2,6-dioxo-oxacyclohexadec-en-8-yl ester 4-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-phenyl ester The solution of 313 mg (0.44 mmol) of the compound, prepared according to Example ELl4a, in 19 ml of ethyl acetate is mixed with 840 mg of the compound that is prepared according to Example L8, 61.5 ~I of triethylamine, and it is stirred for 16 hours at 23°C. It is mixed with water, extracted several times with ethyl acetate, the combined organic extracts are washed with saturated sodium chloride solution and dried over sodium sulfate. The residue that is obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel. 298 mg (348 ~mal, 79%) of the title compound is isolated.
Example EL14 (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-I-yI)-phenyl ester Analogously to Example EL1, 304 mg (355 p.mol) of the compound that is prepared according to Example ELl4a is reacted, and after working-up and purification, 67 mg (90 pmol, 25%) of the title compound is isolated.
1H-NMR (CDCl3): b = 1.09 (3H), I.11 (3H), 0.84-2.02 (7H), 1.27 (3H), 1.72 (3H), 2.29-2.58 (6H), 2.84 (3H), 2.89 (1H), 2.96 (1H), 3.63 (1H), 4.03 (1H), 5.06 (2H), 5.23 (2H), 5.80 (1H), 5.85 (IH), 6.86 (2H), 7.30 (2H), 7.35 (1H), 7.39 (1H), 7.80 (1H), 7.96 ( 1 H) ppm.
Example EL1S

( 1 S,3 S,7S,1 OR,11 S,125,16R)-Carbonic acid-10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-11-yl ester 4-(2,S-dioxo-2,5-dihydro-pyrrol-1-yl)-phenyl ester Analogously to Example EL2, 67 mg (90 ~mol) of the compound that is prepared according to Example EL 14 is reacted, and after working-up and purification, 32 mg (42 ~mol, 47%) of the title compound is isolated.
1H-NMR (CDC13): & = 1.05 (3H), 1.06 (3H), 1.25 (3H), 1.35 (3H), 1.21-1.90 (7H), 2.18 (2H), 2.33-2.67 (4H), 2.73 (1H), 2.85 (3H), 3.79 (1H), 4.11 (1H), 4.33 (1H), 5.02 (1H), 5.07 (1H), 5.31 (1H), 5.81 (1H), 6.27 (1H), 6.86 (2H), 7.29 (2H), 7.35-7.41 l0 (3H), 7.83 (1H), 7.99 (1H) ppm.
Example EL16 (1S,3S(E),7S,lOR,11S,12S,16R)-N [1-(f4-[2-(7,11-Dihydroxy-8,8,10,12,16-pentamethyl-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-3-yl)-propenyl]-thiazol-2-15 ylmethyl}-carbamoyl)-ethyl]-3-methyltrisulfanyl-N methyl-propionamide The solution of 7 mg (13 ~mol) of (1S,3S(E),7S,lOR,11S,12S,16R)-3-[2-(2-aminomethyl-thiazol-4-yl)-1-methyl-vinyl]-7,11-dihydroxy-8,8,10,12,16-penta-methyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione, which was produced analogously to the process described in WO 99/01124, in 0.5 ml of dichloromethane is 20 mixed with 7 mg of the compound that is prepared according to Example L1, 0.4 mg of 4-dimethylaminopyridine and 4 mg of N,N'-dicyclohexylcarbodiimide are added, and it is stirred for 20 minutes at 23°C. Precipitated urea is filtered out, and it is purified by chromatography on a preparative thin-layer plate. 5 mg (6.5 ~mol, 50%) of the title compound is isolated.
25 1H-NMR (CDCl3): 8 =1.00 (3H), 1.08 (3H), 1.17 (3H), 1.23-1.77 (SH), 1.28 (3H), 1.36 (3H), 1.39 (3H), 1.88-2.13 (3H), 2.10 (3H), 2.37 (1H), 2.49-2.66 (2H), 2.55 (3H), 2.77-2.92 (4H), 2.97 (3H), 3.16 (2H), 3.31 (1H), 3.77 (1H), 4.08 (1H), 4.19 (1H), 4.62 (1H), 4.76 (1H), 5.25 (1H), 5.45 (1H), 6.57 (1H), 7.01 (1H), 7.06 (1H) ppm.
30 Example EL17 ( 1 S,3 S(E),75,1 OR,11 S,125,16R)-2-[Methyl-(3-methyltrisulfanyl-propionyl)-amino]-propionic acid-4-[2-(7,11-dihydroxy-8,8,10,12,16-pentamethyl-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-3-yl)-propenyl]-thiazol-2-ylmethyl ester Analogously to Example EL16, 10 mg (19 ~mol) of (1S,3S(E),7S,lOR,llS, 125,16R)-7,11-dihydroxy-3-[2-(2-hydroxymethyl-thiazol-4-yl)-1-methyl-vinyl]-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [ 14.1.0] heptadecane-5,9-dione, which was produced analogously to the process that is described in WO 99/01124, is reacted, and 2.2 mg (2.8 ~mol, 15%) of the title compound is isolated.
1H-NMR (CDC13): 8 =1.Ol (3H), 1.09 (3H), 1.18 (3H), 1.27 (1H), 1.28 (3H), 1.32-1.76 (3H), 1.37 (3H), 1.47 (3H), 1.95 (1H), 2.06 (1H), 2.12 (3H), 2.38 (1H), 2.51-2.63 (2H), 2.56 (3H), 2.78-2.92 (SH), 2.97+3.01 (3H), 3.13-3.35 (3H), 3.71 (1H), 3.77 (1H), 4.00 (1H), 4.18 (1H), 5.25 (1H), 5.39 (2H), 5.45 (1H), 6.60 (1H), 7.17 (1H) ppm.
to Example EL18 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-butanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yloxycarbonyloxymethyl]-2-vitro-phenyl ester Example ELlBa 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-butanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-8-(tart-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yloxycarbonyloxymethyl]-2-2o vitro-phenyl ester Analogously to Example ELl2b, 200 mg (284 pmol) of the compound that is prepared according to Example ELl2a is reacted with 770 mg of the compound that is prepared according to Example L9, and after working-up and purification, 129 mg (129 pmol, 45%) of the title compound is isolated.
Example EL18 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-butanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yloxycarbonyloxymethyl]-2-vitro-phenyl ester 3o Analogously to Example EL1, 129 mg (129 p.mol) of the compound that is prepared according to Example ELl8a is reacted, and after working-up and purification, 71 mg (80 pmol, 62%) of the title compound is isolated.

1H-NMR (CDCl3): 8 = 0.88-2.11 (11H), 1.02 (3H), 1.14 (3H), 1.71 (3H), 2.23-2.56 (6H), 2.63-2.71 (3H), 2.74 (3H), 2.97 (1H), 3.39 (1H), 3.68 (3H), 4.58 (1H), 4.78 (1H), 5.01 (1H), 5.05 (1H), 5.18 (1H), 5.56 (1H), 5.71 (1H), 5.97 (1H), 6.73 (2H), 7.19 (1H), 7.31 (1H), 7.36 (1H), 7.75 (1H), 7.77 (1H), 7.95 (1H) ppm.
Example EL19 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-butanoic acid 4-(1S,3S,7S,lOR,11S,12S,16R)-[10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-7-yloxycarbonyloxymethyl]-2-vitro-phenyl ester (A) and 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-butanoic acid 4-(1 R,3 S,7S,1 OR,11 S,12S,16S)-[10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzotluazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo [ 14.1.0]heptadec-7-yloxycarbonyloxymethyl]-2-vitro-phenyl ester (B) Analogously to Example EL2, 71 mg (80 ~mol) of the compound that is prepared according to Example EL18 is reacted, and after working-up and purification, 41 mg (45 pmol, 57%) of title compound A as well as 12 mg (13 p.mol,17%) of title compound B are isolated.
1H-NMR (CDCl3) of A: 8 =1.04 (3H), 1.14 (3H), 1.16 (3H), 1.32 (3H), 1.34-1.84 (6H), 2.01-2.74 (12H), 2.78 (3H), 2.86 (1H), 3.44 (1H), 3.68 (3H), 4.56 (1H), 4.74 (iH), 5.01 (1H), 5.06 (1H), 5.47 (iH), 5.70 (1H), 6.07 (1H), 6.73 (2H), 7.20 (1H), 7.32 (1H), 7.36 (1H), 7.77 (1H), 7.81 (1H), 7.90 (1H) ppm.
Example EL20 6-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yloxycarbonyloxymethyl]-2-vitro-phenyl ester Example EL20a 6-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-3o allyl-8-(tent-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yloxycarbonyloxymethyl]-2-vitro-phenyl ester Analogously to Example ELl2b, 243 mg (345 ~mol) of the compound that is prepared according to Example ELl2a is reacted with 1 g of the compound that is prepared according to Example L10, and after working-up and purification, 25 mg (24 ~,mol, 7%) of the title compound is isolated.
Example EL20 6-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yloxycarbonyloxymethylJ-2-vitro-phenyl ester 1o Analogously to Example EL1, 212 mg (206 ~mol) of the compound that is prepared according to Example EL20a is reacted, and after working-up and purification, 117 mg (128 ~mol, 62%) of the title compound is isolated.
1H NMR (CDCl3): b =1.01 (3H), 1.14 (6H), 1.04-2.78 (20H), 1.70 (3H), 2.74 (3H), 2.97 (1H), 3.39 (1H), 3.56 (2H), 3.68 (1H), 4.11 (1H), 4.58 (1H), 4.77 (1H), 5.00 15 (1H), 5.05 (1H), 5.18 (1H), 5.56 (1H), 5.71 (1H), 5.97 (1H), 6.69 (2H), 7.12 (1H), 7.29 (1H), 7.36 (1H), 7.75 (2H), 7.94 (1H) ppm.
Example EL21 6-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoic acid 4-(1S,3S,7S,lOR,11S,12S,16R)-20 [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-yloxycarbonyloxymethylJ-2-vitro-phenyl ester (A) and 6-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoic acid 4-(1R,3 S,7S, l OR,11 S,125,16S)-[10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo [ 14.1.OJheptadec-7-25 yloxycarbonyloxymethyl]-2-vitro-phenyl ester (B) Analogously to Example EL2, 117 mg (128 ~mol) of the compound that is prepared according to Example EL20 is reacted, and after working-up and purification, 63 mg (68 p.mol, 53%) of title compound A as well as 19 mg (20 ~.mol, 16%) of title compound B are isolated.
30 1H-NMR (CDC13) of A: b =1.03 (3H), 1.14 (3H), 1.15 (3H), 1.32 (3H), 1.07-2.75 (22H), 2.77 (3H), 2.86 (1H), 3.44 (1H), 3.55 (2H), 3.69 (1H), 4.55 (1H), 4.77 (1H), 5.01 (1H), 5.06 (1H), 5.47 (1H), 5.70 (1H), 6.08 (1H), 6.70 (2H), 7.14 (1H), 7.31 (1H), 7.35 (1H), 7.76 (1H), 7.80 (1H), 7.90 (1H) ppm.

Example EL22 11-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-undecanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yloxycarbonyloxymethyl]-2-vitro-phenyl ester Example EL22a 11-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-undecanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-8-(tart-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-l0 benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yloxycarbonyloxymethyl]-2-vitro-phenyl ester Analogously to Example ELl2b, 243 mg (345 ~.mol) of the compound that is prepared according to Example ELl2a is reacted with 1.19 g of the compound that is prepared according to Example L11, and after working-up and purification, 171 mg is (155 ~mol, 45%) of the title compound is isolated.
Example EL22 11-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-undecanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-20 oxacyclohexadec-13-en-4-yloxycarbonyloxymethyl]-2-vitro-phenyl ester Analogously to Example EL1, 171 mg (155 ~mol) of the compound that is prepared according to Example EL22a is reacted, and after working-up and purification, 108 mg (110 ~.mol, 71%) of the title compound is isolated.
1H-NMR (CDC13): 8 =1.02 (3H), 1.14 (6H), 0.88-2.56 (28H), 1.70 (3H), 2.63 25 (2H), 2.71 (1H), 2.74 (3H), 2.98 (1H), 3.39 (1H), 3.50 (2H), 3.69 (1H), 4.58 (1H), 4.77 (1H), 5.00 (1H), 5.05 (1H), 5.17 (1H), 5.56 (1H), 5.71 (1H), 5.97 (1H), 6.68 (2H), 7.11 (1H), 7.29 (1H), 7.36 (1H), 7.75 (1H), 7.76 (1H), 7.94 (1H) ppm.
Example EL23 30 11-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-undecanoic acid 4-(1 S,3 S,7S, l OR,11 S,125,16R)-[ 10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo [ 14.1.0]heptadec-7-yloxycarbonyloxymethyl]-2-vitro-phenyl ester (A) and 11-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-undecanoic acid 4-(IR,3S,7S,lOR,11S,12S, 16S)-[10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-S-yl)-S,9-dioxo-4, I7-dioxa-bicyclo[14.1.0]heptadec-7-yloxycarbonyloxymethyl]-2-vitro-phenyl ester (B) Analogously to Example EL2, 108 mg (110 ~.mol) of the compound that is prepared according to Example EL22 is reacted, and after working-up and purification, 65.9 mg (65.8 pmol, 60%) of title compound A as well as 19.8 mg (20 ~,mol, 18%) of title compound B are isolated.
1H-NMR (CDC13) of A: 8 = 1.04 (3H), 1.14 (3H), 1.15 (3H), 1.63 (3H), 0.92-1.85 (23H), 2.10-2.8I (9H), 2.77 (3H), 2.86 (1H), 3.45 (1H), 3.51 (2H), 3.69 (1H), 4.SS (1H), 4.74 (1H), S.O1 (1H), 5.06 (1H), 5.47 (1H), 5.70 (1H), 6.08 (1H), 6.68 (2H), 7.13 (I H), 7.3 I (1 H), 7.3 S (1 H), 7.77 (1 H), 7.80 ( 1 H), 7.90 (1 H) ppm.
Example EL24 4-(2,S-Dioxo-2,S-dihydro-pyrrol-1-yl)-butanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-2-vitro-phenyl ester Example EL24a 4-(2,S-Dioxo-2,S-dihydro-pyrrol-1-yl)-butanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-2o allyl-4-(tart-butyl-dimethyl-silanyloxy)-S,S,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-2-vitro-phenyl ester Analogously to Example ELl2b, 271 mg (38S p.mol) of the compound that is prepared according to Example ELl4a is reacted with 1.04 g of the compound that is prepared according to Example L9, and after working-up and purification, 193 mg (193 pmol, SO%) of the title compound is isolated.
Example EL24 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-butanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-3o allyl-4-hydroxy-S,S,9,13-tetramethyl-16-(2-methyl-benzothiazol-S-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-2-vitro-phenyl ester Analogously to Example ELl, 193 mg (193 ~,mol) of the compound that is prepared according to Example EL24a is reacted, and after working-up and purification, 107 mg (120 ~,mol, 62%) of the title compound is isolated.
1H-NMR (CDCl3): 8 = 1.02 (3H), 1.07 (3H), 1.23 (3H), 0.97-2.13 (8H), 1.71 (3H), 2.28-2.54 (6H), 2.67 (2H), 2.84 (3H), 2.88 (1H), 2.95 (1H), 3.56 (1H), 3.67 (2H), 4.01 (IH), 4.93 (1H), 4.98 (1H), 5.17 (1H), 5.22 (3H), 5.70 (1H), 5.84 (1H), 6.72 (2H), 7.30 (1H), 7.34 (1H), 7.69 (1H), 7.80 (1H), 7.95 (1H), 8.13 (1H) ppm.
Example EL25 10 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-butanoic acid 4-(1S,3S,7S,lOR,11S,12S,16R)-[ I 0-allyl-7-hydroxy-8,8,12, I 6-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-11-yloxycarbonyloxymethyl]-2-nitro-phenyl ester (A) and 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-butanoic acid 4-( 1 R,3 S,7 S, l OR,11 S,12S,16S)-[ 10-allyl-7-hydroxy-8, 8,12,16-tetramethyl-3 -(2-methyl-15 benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-11-yloxycarbonyloxymethyl]-2-vitro-phenyl ester (B) Analogously to Example EL2, 102 mg (115 ~.mol) of the compound that is prepared according to Example EL19 is reacted, and after working-up and purification, 65 mg (72 ~mol, 63%) of title compound A as well as 3 mg (3.3 ~.mol, 3%) of title 2o compound B are isolated.
1H-NMR (CDC13) of A: 8 = 0.97 (3H), 1.04 (3H), 1.23 (3H), 1.31 (3H), 1.10-2.75 (18H), 2.85 (3H), 3.68 (2H), 3.71 (1H), 4.09 (1H), 4.28 (1H), 4.92 (1H), 4.97 (1H), 5.20 (2H), 5.23 (IH), 5.72 (1H), 6.26 (IH), 6.72 (2H), 7.30 (1H), 7.37 (1H), 7.68 (1H), 7.83 (1H), 7.98 (1H), 8.13 (IH) ppm.
Example EL26 6-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yI)-2,6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-2-vitro-phenyl ester Example EL26a 6-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-4-(tart butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-2-nitro-phenyl ester Analogously to Example ELl2b, 273 mg (387 ~mol) of the compound that is prepared according to Example ELl4a is reacted with 1.12 g of the compound that is prepared according to Example L 10, and after working-up and purification, 69 mg (67 pmol, 17%) of the title compound is isolated.
Example EL26 6-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoic acid 4-(4S,7R,8S,9S,I3Z,16S)-[7-lo allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-2-vitro-phenyl estex Analogously to Example ELI, 69 mg (67 p.mol) of the compound that is prepared according to Example EL26a is reacted, and after working-up and purification, 26 mg (28 p,mol, 42%) of the title compound is isolated.
is 1H-NMR (CDCl3): b = 0.93 (3H), 0.95 (3H), I.16 (3H), 1.60 (3H), 0.98-2.61 (20H), 2.73 (3H), 2.77 (1H), 3.45 (3H), 3.83 (1H), 4.05 (1H), 4.83 (1H), 4.88 (IH), 5.05 ( 1 H), 5. I 3 (3 H), 5.62 ( 1 H), 5.74 ( 1 H), 6.61 (2H), 7. I 6 ( 1 H), 7.26 ( 1 H), 7.60 ( 1 H), 7.70 (1H), 7.88 (1H), 8.03 (1H) ppm.
2o Example EL27 6-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoic acid 4-(1S,3S,7S,lOR,11S,12S,16R)-[10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.I.0]heptadec-11-yloxycarbonyloxymethyl]-2-vitro-phenyl ester (A) and 6-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yI)-hexanoic acid 4-25 (1R,3S,7S,IOR,11S,12S,16S)-[IO-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo [ I 4. I .0] heptadec-1 I -yloxycarbonyloxymethyl]-2-nitxo-phenyl ester (B) Analogously to Example EL2, 38 mg (41 ~mol) of the compound that is prepared according to Example EL19 is reacted, and after working-up and purification, 30 14 mg (15 p,mol, 37%) of title compound A as well as 2 mg (2 gmol, 5%) of title compound B are isolated.
IH-NMR (CDCl3) of A: 8 = 0.96 (3H), I.03 (3H), 1.08-1.86 (13H), 1.23 (3H), 1.30 (3H), 2.16 (2H), 2.23-2.78 (7H), 2.83 (3H), 3.54 (2H), 3.71 (1H), 4.09 (1H), 4.27 ( 1 H), 4.9 I ( 1 H), 4.96 ( 1 H), 5.21 (3 H), 5.72 ( 1 H), 6.25 ( 1 H), 6.69 (2H), 7.23 ( 1 H), 7.3 6 (1H), 7.67 (IH), 7.82 (1H), 7.96 (1H), 8.11 (1H) ppm.
Example EL28 11-(2,S-Dioxo-2,S-dihydro-pyrrol-1-yl)-undecanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-2-vitro-phenyl ester Example EL28a l0 11-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-undecanoic acid 4-(4S,7R,8S,9S,I3Z,16S)-[7-allyl-4-(test-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-S-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-2-vitro-phenyl ester Analogously to Example ELl2b, 273 mg (387 ~,mol) of the compound that is 15 prepared according to Example ELl4a is reacted with 1.34 g of the compound that is prepared according to Example Ll l, and after working-up and purification, 196 mg (178 ~.mol, 46%) of the title compound is isolated.
Example EL28 20 11-(2,5-Dioxo-2,5-dihydro-pyrrol-I-yl)-undecanoic acid 4-(4S,7R,8S,9S,13Z,I6S)-[7-allyl-4-hydroxy-S,S,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-2-vitro-phenyl ester Analogously to Example ELl, 196 mg (178 pmol) of the compound that is prepared according to Example EL28a is reacted, and after working-up and 25 purification, 100 mg (101 pmol, 57%) of the title compound is isolated.
1H-NMR (CDC13): b =1.03 (3H), 1.06 (3H), 1.23 (3H), 1.70 (3H), 0.99-1.81 (21H), 1.91 (IH), 2.27-2.53 (6H), 2.63 (2H), 2.83 (3H), 2.88 (1H), 2.95 (1H), 3.51 (2H), 3.56 (IH), 4.00 (1H), 4.92 (IH), 4.98 (IH), 5.13-5.26 (4H), 5.71 (1H), 5.83 (1H), 6.68 (2H), 7.23 (1H), 7.34 (1H), 7.67 (1H), 7.79 (1H), 7.95 (IH), 8.13 (1H) ppm.
Example EL29 11-(2,S-Dioxo-2,5-dihydro-pyrrol-I-yl)-undecanoic acid 4-( 1 S,3 S,7S,1 OR,11 S,12S,16R)-[ 10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo [ 14.1.0]heptadec-1 I -yloxycarbonyloxymethyl]-2-vitro-phenyl ester (A) and 11-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-undecanoic acid 4-(1R,3S,7S,lOR,lIS, 125,16S)-[ 10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-11-yloxycarbonyloxymethyl]-2-nitro-phenyl ester (B) Analogously to Example EL2, I00 mg (101 ~mol) of the compound that is prepared according to Example EL19 is reacted, and after working-up and purification, 21 mg (21 ~mol, 21 %) of title compound A as well as 2 mg (2 pmol, 2%) of title to compound B are isolated.
1H-NMR (CDC13) of A: b = 0.97 (3H), 1.04 (3H), 1.23 (3H), 0.84-1.84 (24H), 1.71 (3H), 2.15 (2H), 2.23-2.68 (SH), 2.71 (1H), 2.83 (3H), 3.50 (2H), 3.71 (1H), 4.09 (1H), 4.27 (1H), 4.91 (1H), 4.96 (1H), 5.19 (2H), 5.23 (1H), 5.72 (1H), 6.26 (1H), 6.68 (2H), 7.23 (1H), 7.36 (1H), 7.66 (1H), 7.83 (1H), 7.97 (1H), 8.12 (1H) ppm, IS
Example EL30 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-butanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-I3-en-4-yloxycarbonyloxymethyl]-phenyl ester Example EL30a 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-butanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-8-(tert-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-I3-en-4-yloxycarbonyloxymethyl]-phenyl ester Analogously to Example ELl2b, 218 mg (309 ~mol) of the compound prepared according to Example ELl2a are reacted with 314 mg of the compound prepared according to Example L12. After working-up and purification, 103 mg (118 ~.mol, 35%) of the title compound are isolated.
Example EL30 4-(2,5-Dioxo-2,S-dihydro-pyrrol-1-yl)-butanoic acid 4-(4S,7R,8S,9S,I3Z,16S)-[7-allyl-8-hydroxy-S,S,9,13-tetramethyl-16-(2-methyl-benzothiazol-S-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yloxycarbonyloxymethyl]-phenyl ester Analogously to Example EL1, I03 mg (118 ~,mol) of the compound prepared according to Example EL30a are reacted. After working-up and purification, 13 mg (15 ~mol, 13%) of the title compound are isolated.
1H-NMR (CDC13): b= 0.88-1.84 (7H), 1.00 (3H), 1.12 (3H), 1.14 (3H), 1.71 (3H), 2.04 (2H), 2.23-2.71 (8H), 2.74 (3H), 2.99 (1H), 3.40 (1H), 3.67 (3H), 4.48 (IH), 4.76 (IH), 5.00 (IH), 5.04 (1H), 5.18 (1H), S.SS (1H), 5.71 (1H), 5.98 (1H), 6.72 (2H), 7.01 (2H), l0 7.08 (2H), 7.37 (1H), 7.76 (1H), 7.96 (1H) ppm.
Example EL31 4-(2,S-Dioxo-2,S-dihydro-pyrrol-1-yl)-butanoic acid 4-(1S,3S,7S,lOR,11S,12S, 16R)-[10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-S-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-7-yloxycarbonyloxymethyl]-phenyl ester Analogously to Example EL2, 13 mg (15 ~.mol) of the compound prepared according to Example EL30 are reacted. After working-up and purification, S.7 mg (6.6 pmol, 44%) of the title compound are isolated.
~H-NMR (CDCl3) of A: 8 = 1.04 (3H), 1.14 (3H), 1.16 (3H), 1.32 (3H), 1.34-1.84 (6H), 2.04 (2H), 2.15-2.75 (10H), 2.78 (3H), 2.85 (1H), 3.44 (1H), 3.67 (3H), 4.48 (1H), 4.73 (1H), S.O1 (1H), S.OS (1H), 5.47 (1H), 5.70 (1H), 6.07 (1H), 6.72 (2H), 7.02 (2H), 7.13 (2H), 7.31 ( 1 H), 7.77 ( I H), 7.93 ( 1 H) ppm.
Example EL32 6-(2,S-Dioxo-2,S-dihydro-pyrrol-1-yl)-hexanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-8-hydroxy-5,5,9,I3-tetramethyl-16-(2-methyl-benzothiazol-S-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yloxycarbonyloxymethyl]-phenyl ester Example EL32a 6-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-8-(tert-butyl-dimethyl-silanyloxy)-S,S,9,13-tetramethyl-16-(2-methyl-benzothiazol-S-yI)-2,6-dioxo-oxacyclohexadec-13-en-4-yloxycarbonyloxymethyl]-phenyl ester Analogously to Example ELl2b, 218 mg (309 ~mol) of the compound prepared according to Example ELl2a are reacted with 396 mg of the compound prepared according to Example L13. After working-up and purification, 157 mg (159 ~mol, S 1 %) of the title compound are isolated.

Example EL32 6-(2,S-Dioxo-2,S-dihydro-pyrrol-1-yl)-hexanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yloxycarbonyloxymethyl]-phenyl ester to Analogously to Example ELI, 157 mg (1S9 ~.mol) of the compound prepared according to Example EL32a are reacted. After working-up and purification, 32 mg (37 ~mol, 23%) ofthe title compound are isolated.
iH-NMR (CDCI3): 8 = 0.99 (3H), 1.12 (3H), 1.14 (3H), 1.04-2.84 (20H), 1.70 (3H), 2.75 (3H), 3.00 (1H), 3.40 (1H), 3.55 (2H), 3.68 (1H), 4.48 (1H), 4.76 (1H), 5.00 (1H), Is 5.04 (1H), 5.18 (1H), S.SS (1H), 5.71 (1H), 5.98 (1H), 6.69 (2H), 6.98 (2H), 7.07 (2H), 7.37 (1H), 7.76 (2H), 7.96 (1H) ppm.
Example EL33 6-(2,S-Dioxo-2,5-dihydro-pyrrol-l,-yl)-hexanoic acid 4-(1S,3S,78,1OR,11S,12S, 16R)-20 [10-allyl-I1-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-S-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-7-yloxycarbonyloxymethyl]-phenyl ester Analogously to Example EL2, 30 mg (34 ~Cmol) of the compound prepared according to Example EL32 are reacted. After working-up and purification, 13 mg (15 ~.mol, 44%) of the title compound are isolated.
~5 1H-NMR (CDCl3) of A: ~ = 1.01 (3H), 1.13 (3H), 1.14 (3H), 1.32 (3H), 1.07-2.75 (22H), 2.78 (3H), 2.85 (1H), 3.44 (1H), 3.55 (2H), 3.69 (1H), 4.48 (1H), 4.73 (1H), S.Ol (1H), 5.05 (1H), 5.45 (1H), 5.70 (1H), 6.08 (1H), 6.69 (2H), 6.99 (2H), 7.12 (2H), 7.32 ( 1 H), 7.77 ( 1 H), 7.92 ( 1 H) ppm.
3o Example EL34 11-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-undecanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-8-hydroxy-S,S,9,13-tetramethyl-16-(2-methyl-benzothiazol-S-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yloxycarbonyloxymethyl]-phenyl ester Example EL34a II-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-undecanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-8-(tart-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yloxycarbonyloxymethyl]-phenyl ester Analogously to Example ELl2b, 218 mg (309 ~.mol) of the compound prepared according to Example ELl2a are reacted with 422 mg of the compound prepared according to Example L 14. After working-up and purification, 77 mg (73 ~mol, 24%) to of the title compound are isolated.
Example EL34 11-(2,s-Dioxo-2,S-dihydro-pyrrol-1-yl)-undecanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-8-hydroxy-5,5,9,13-tetramethyl-I 6-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-1s oxacyclohexadec-13-en-4-yloxycarbonyloxymethyl]-phenyl ester Analogously to Example EL1, 77 mg (73 ~mol) of the compound prepared according to Example EL34a are reacted. After working-up and purification, 14 mg (15 ~mol, 20%) of the title compound are isolated.
1H-NMR (CDCl3): 8 = 0.99 (3H), I.11 (3H), 1.14 (3H), 0.88-1.88 (22H), 1.70 (3H), 20 2.24-2.58 (8H), 2.67 (1H), 2.75 (3H), 3.00 (1H), 3.40 (1H), 3.51 (2H), 3.68 (IH), 4.48 (1H), 4.76 (1H), 5.00 (1H), 5.04 (1H), 5.18 (1H), 5.55 (1H), 5.71 (1H), 5.98 (1H), 6.68 (2H), 6.98 (2H), 7.07 (2H), 7.37 (1H), 7.76 (1H), 7.96 (IH) ppm.
Example EL35 2s 11-(2,5-Dioxo-2,5-dihydro-pyrrol-I-yl)-undecanoic acid 4-(1S,3S,7S,lOR,11S,12S, 16R)-(10-allyl-11-hydroxy-8,8,12,16-tetxamethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,I7-dioxa-bicyclo[14.1.0]heptadec-7-yloxycarbonyloxymethyl]-phenyl ester Analogously to Example EL2, 14 mg ( 15 ~,mol) of the compound prepared according to Example EL34 are reacted. After working-up and purification, 6 mg ( 6 ~.mol, 42%) 3o of the title compound are isolated.
1H-NMR (CDCl3) von A: 8 = 1.01 (3H), 1.14 (6H), 1.20-1.90 (26H), 2.12-2.58 (8H), 2.71 (1H), 2.77 (3H), 2.85 (IH), 3.44 (IH), 3.SI (2H), 3.69 (IH), 4.48 (1H), 4.73 (1H), 5.01 (1H), S.OS (1H), 5.45 (1H), 5.70 (1H), 6.08 (1H), 6.68 (2H), 6.99 (2H), 7.12 (2H), 7.31 (1H), 7.77 (1H), 7.92 (1H) ppm.
Example EL36 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-butanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yI)-2,6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-phenyl ester Example EL36a l0 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-butanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-4-(tent-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-S-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-phenyl ester Analogously to Example ELl2b, 330 mg (470 p,mol) of the compound prepared according to Example ELl4a are reacted with 544 mg of the compound prepared according to Example L12. After working-up and purification, 170 mg (178 ~.mol, 38%) of the title compound are isolated.
Example EL36 4-(2,S-Dioxo-2,S-dihydro-pyrrol-I-yI)-butanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-S-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-phenyl ester Analogously to Example EL1, 170 mg (178 pmol) of the compound prepared according to Example EL36a are reacted. After working-up and purification, 21 mg (24 pmol, 14%) of the title compound are isolated.
1H-NMR (CDC13): 8 = I.02 (3H), 1.07 (3H), 1.22 (3H), 0.97-2.13 (BIB, 1.70 (3H), 2.28-2.63 (8H), 2.84 (3H), 2.82-2.95 (2H), 3.SS (1H), 3.67 (2H), 3.97 (1H), 4.92 (1H), 4.96 (1H), S.1S (IH), 5.16 (2H), 5.22 (1H), 5.70 (1H), 5.82 (1H), 6.68 (2H), 7.08 (2H), 7.34 (1H), 7.41 (2H), 7.79 (1H), 7.94 (1H) ppm.
Example EL37 4-(2,5-Dioxo-2,S-dihydro-pyrrol-1-yl)-butanoic acid 4-(1S,3S,7S,lOR,11S,12S, 16R)-[ 10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-S-yl)-S,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-11-yloxycaxbonyloxymethyl]-2-nitro-phenyl ester (A) and 4-(2,S-Dioxo-2,S-dihydro-pyrrol-1-yl)-butanoic acid 4-(1R,3S,7S,lOR,11S,12S,16S)-[10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-11-yloxycarbonyloxymethyl]-phenyl ester (B) 32 mg (38p.mo1) of the compound prepared according to Example EL36 are reacted.
After working-up and purification, 10.1 mg ( 12 p,mol, 31%) of title compound A as well as 1.2 mg (1.4 ~,mol, 3,7%) of title compound B are isolated.
IH-NMR (CDC13) of A: 8 = 0.96 (3H), 1.04 (3H), 1.24 (3H), 1.29 (3H), 0.90-1.78 to (7H), 2.04 (2H), 2.16 (2H), 2.20-2.62 (6H), 2.72 (1H), 2.84 (3H), 3.67 (2H), 3.69 (1H), 4.07 (1H), 4.20 (1H), 4.91 (1H), 4.95 (1H), 5.14 (2H), 5.22 (1H), 5.72 (1H), 6.24 (1H), 6.71 (2H), 7.10 (2H), 7.37 (1H), 7.40 (2H), 7.88 (1H), 7.97 (1H) ppm.
Example EL3 8 6-(2,S-Dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7 allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yI)-2,6-dioxo oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-phenyl ester Example EL38a 6-(2,5-Dioxo-2,S-dihydro-pyrrol-1-yl)-hexanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-4-(tert-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-phenyl ester Analogously to Example ELl2b, 450 mg (640 ~mol) of the compound prepared according to Example ELl4a are reacted with 811 mg of the compound prepared according to Example L13. After working-up and purification, 108 mg (110 ~.mol, 17%) of the title compound are isolated.
Example EL38 6-(2,5-Dioxo-2,S-dihydro-pyrrol-1-yl)-hexanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7 allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-phenyl ester 108mg (l I0 pmol) of the compound prepared according to Example EL38a in 22 ml dichloromethane are mixed with 1.06 ml (2.74 mmol) of a 20% solution of trifluoroacetic acid in dichloromethane. After 16 hours the mixture is diluted with dichloromethane and poured into a saturated solution of sodium bicarbonate.
The s mixture is extracted several times with dichloromethane and the combined organic extracts are dried over sodium sulfate. The residue obtained by filtration and removal of the solvent is purified by chromatography on fine silica gel. 64 mg (73 pmmol, 67%) of the title compound are isolated.
IH-NMR (CDCl3): 8 = 1.02 (3H), 1.07 (3H), I.16 (3H), 1.70 (3H), 0.98-1.96 (12H), l0 2.25-2.58 (8H), 2.83 (3H), 2.90 (2H), 3.55 (3H), 3.97 (1H), 4.92 (1H), 4.96 (1H), 5.15 (1H), 5.16 (2H), 5.22 (IH), 5.70 (1H), 5.82 (1H), 6.69 (2H), 7.08 (2H), 7.34 (1H), 7.41 (2H), 7.79 ( 1 H), 7.94 ( 1 H) ppm.
Example EL39 15 6-(2,S-Dioxo-2,S-dihydro-pyrrol-I-yl)-hexanoic acid 4-(1S,3S,7S,lOR,l IS,I2S, 16R)-[ 10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-S-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-I 1-yloxycarbonyloxymethyl]-phenyl ester (A) and 6-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoic acid 4-(1R,3S,7S,lOR,11S,12S,I6S)-[10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-20 4,17-dioxa-bicyclo[14.1.0]heptadec-11-yloxycarbonyloxymethyl]-phenyl ester (B) Analogously to Example EL2, 64 mg (73 p.mol) of the compound pxepared according to Example EL38 are reacted. After working-up and purification, 25 mg (28 ~.mol, 39%) of the title compound A as well as 5.4 mg (6.1 pmol, 8.3%) of the title compound B are isolated.
25 iH-NMR (CDCl3) of A: b = 0.96 (3H), 1.04 (3H), 1.13-1.82 (13H), 1.23 (3H), 1.29 (3H), 2.15 (2H), 2.22-2.64 (6H), 2.71 (1H), 2.84 (3H), 3.54 (2H), 3.69 (1H), 4.08 (1H), 4.20 ( 1 H), 4.91 ( 1 H), 4.9 S ( 1 H), 5.14 (2H), 5.22 ( 1 H), 5.72 ( 1 H), 6.24 ( 1 H), 6.69 (2H), 7.07 (2H), 7.3 7 ( 1 H), 7.40 (2H), 7. 82 ( 1 H), 7.97 ( 1 H) ppm.
3o Example EL40 11-(2,5-Dioxo-2,S-dihydro-pyrrol-1-yl)-undecanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-phenyl ester Example EL40a 11-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-undecanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-4-(tert-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-5 benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-phenyl ester Analogously to Example ELl2b, 450 mg (640 ~,mol) of the compound prepared according to Example ELl4a are reacted with 992 mg of the compound prepared according to Example L 14. After working-up and purification, 67 mg (63 pmol, 10%) to of the title compound are isolated.
Example EL40 11-(2,S-Dioxo-2,5-dihydro-pyrrol-1-yl)-undecanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-15 oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-phenyl ester Analogously to Example EL38, 67 mg (63 ~mol) of the compound prepared according to Example EL40a are reacted. After working-up and purification, 23 mg (24 p,mol, 38%) of the title compound are isolated.
IH-NMR (CDCl3): 8 = 1.02 (3H), 1.07 (3H), 1.21 (3H), 1.70 (3H), 0.99-1.81 (21H), 20 1.91 (1H), 2.27-2.58 (8H), 2.83 (3H), 2.89 (2H), 3.50 (2H), 3.55 (1H), 3.97 (1H), 4.92 (1H), 4.96 (1H), 5.15 (1H), 5.16 (2H), 5.20 (1H), 5.70 (1H), 5.82 (1H), 6.68 (2H), 7.08 (2H), 7.34 (1H), 7.41 (2H), 7.79 (1H), 7.94 (1H) ppm.
Example EL41 25 11-(2,S-Dioxo-2,5-dihydro-pyrrol-1-yl)-undecanoic acid 4-(1S,3S,7S,lOR,11S,12S, 16R)-[10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-11-yloxycarbonyloxyrnethyl]-phenyl ester (A) and 11-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-undecanoic acid 4-(1 R,3 S,7S, l OR,11 S,125,16S)-[10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-3o benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-lI-yloxycarbonyloxyrnethyl]-phenyl ester (B) Analogously to Example EL2, 33 mg (35 p.mol) of the compound prepared according to Example EL40 are reacted. After working-up and purification, 13 mg ( 14 ~mol, 38%) of the title compound A as well as 4 mg (4 ~.mol, 12%) of the title compound B
are isolated.
iH-NMR (CDCI3) of A: S = 0.96 (3H), 1.04 (3H), 1.23 (3H), 0.91-1.78 (27H), 2.16 (2H), 2.23-2.68 (SH), 2.71 (IH), 2.84 (3H), 3.50 (2H), 3.69 (1H), 4.07 (1H), 4.20 (1H), 4.9 I ( 1 H), 4.95 ( 1 H), 5.14 (2H), 5.22 ( 1 H), 5.72 ( I H), 6.24 ( 1 H), 6.68 (2H), 7.07 (2H), 7.37 (1H), 7.40 (2H), 7.82 (1H), 7.97 (1H) ppm.
Example EL42 4-(2,S-Dioxo-2,S-dihydro-pyrrol-1-yl)-butanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7 lo allyl-8-hydroxy-S,S,9,13-tetramethyl-16-(2-methyl-benzothiazol-S-yl)-2,6-dioxo oxacyclohexadec-13-en-4-yloxycarbonyloxymethyl]-2-chlor-phenyl ester Example EL42a 4-(2,S-Dioxo-2,S-dihydro-pyrrol-1-yl)-butanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-8-(tert-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-S-y1)-2,6-dioxo-oxacyclohexadec-13-en-4-yloxycarbonyloxymethyl]-2-chlor-phenyl ester Analogously to Example ELl2b, 329 mg (467~mo1) of the compound prepared according to Example ELl2a are reacted with 885 mg of the compound prepared 2o according to Example L1S. After working-up and purification, 126 mg (127 p,mol, 27%) of the title compound are isolated.
Example EL42 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-butanoic acid 4-(4S,7R,8S,9S,I3Z,16S)-[7 allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-S-yl)-2,6-dioxo oxacyclohexadec-13-en-4-yloxycarbonyloxymethyl]-2-chlor-phenyl ester Analogously to Example EL1, I26 mg (127 p.mol) of the compound prepared according to Example EL42a are reacted. After working-up and purification, 79 mg (90 p,mol, 71 %) of the title compound are isolated.
3o iH-NMR (CDCI3): 8 = 1.01 (3H), 1.13 (3H), I.14 (3H), I.70 (3H), 1.31-1.72 (17H), 2.75 (3H), 2.99 (1H), 3.40 (1H), 3.68 (3H), 4.49 (1H), 4.70 (1H), 5.00 (1H), 5.05 (1H), 5.18 (1H), S.SS (1H), 5.71 (1H), 5.98 (1H), 6.72 (2H), 6.99 (1H), 7.07 (1H), 7.I0 (1H), 7.36 (1H), 7.75 (1H), 7.95 (1H) ppm.

Example EL43 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-butanoic acid 4-(1S,3S,7S,lOR,11S,12S, 16R)-[10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-7-yloxycarbonyloxymethyl]-2-chlor-phenyl ester (A) and 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-butanoic acid 4-( 1 R,3 S,7S,10R,11 S, I2S, 16S)-[ 10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo [ 14.1.0]heptadec-7-yloxycarbonyloxymethyl]-2-chlor-phenyl ester (B) to Analogously to Example EL2, 66 mg (75 ~,mol) of the compound prepared according to Example EL42 are reacted. After working-up and purification, 29.4 mg (32.9pmol, 44%) of the title compound A as well as 9.7 mg (10.9 ~mol, 14%) of the title compound B are isolated.
1H-NMR (CDCl3) of A: cS = 1.03 (3H), 1.13 (3H), 1.15 (3H), I.23 (1H), 1.3I
(3H), 1.34-2.74 (17H), 2.78 (3H), 2.86 (1H), 3.44 (1H), 3.67 (3H), 4.46 (1H), 4.67 (1H), 5.01 (1H), 5.05 (1H), 5.46 (1H), 5.70 (1H), 6.08 (1H), 6.72 (2H), 7.01 (IH), 7.08 (IH), 7.16 ( 1 H), 7.31 ( 1 H), 7.77 ( 1 H), 7.92 ( 1 H) ppm.
Example EL44 6-(2,5-Dioxo-2,5-dihydro-pyrrol-I-yl)-hexanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yloxycarbonyloxymethyl]-2-chloro-phenyl ester Example EL44a 6-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-8-(tert-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yloxycarbonyloxymethyl]-2-chloro-phenyl ester Analogously to Example ELl2b, 329 mg (467 p,mol) of the compound prepared 3o according to Example ELl2a are reacted with 821 mg of the compound prepared according to Example L16. After working-up and purification, 120 mg (118 ~mol, 25%) of the title compound are isolated.

Example EL44 6-(2,S-Dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-8-hydroxy-S,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yloxycarbonyloxymethyl]-2-chloro-phenyl ester Analogously to Example EL1, 120 mg (118 ~,mol) of the compound prepared according to Example EL44a are reacted. After working-up and purification, 60 mg (66 ~mol, 56%) of the title compound are isolated.
1H NMR (CDCl3): 8 = 1.01 (3H), 1.05 (1H), 1.13 (3H), 1.14 (3H), 1.33-1.89 (12H), 1.7I (3H), 2.24-2.70 (8H), 2.74 (3H), 3.00 (1H), 3.40 (1H), 3.55 (2H), 3.69 (1H), 4.49 ~o (1H), 4.71 (1H), 5.00 (1H), 5.05 (1H), 5.18 (1H), 5.56 (1H), 5.71 (iH), 5.99 (1H), 6.70 (2H), 6.95 (1H), 7.03 (IH), 7.11 (1H), 7.37 (1H), 7.75 (1H), 7.95 (1H), ppm.
Example EL45 6-(2,S-Dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoic acid 4-(1S,3S,7S,lOR,11S,12S, 16R)-[IO-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-7-yloxycarbonyloxymethyl]-2-chloro-phenyl ester (A) and 6-(2,S-Dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoic acid 4-(1R,3S,7S,10R,11S,12S, 16S)-[10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[ 14. I .0]heptadec-7-2o yloxycarbonyloxymethyl]-2-chloro-phenyl ester (B) Analogously to Example EL2, 60 mg (66 ~mol) of the compound prepared according to Example EL44 is reacted. After working-up and purification, 32 mg (34.7 ~,mol, 53%) of the title compound A as well as 11 mg (11.9 pmol, I8%) of the title compound B are isolated.
IH-NMR (CDCl3) von A: b = 1.02 (3H), 1.14 (3H), 1.15 (3H), 1.24 (1H), 1.32 (3H), 1.34-2.74 (21H), 2.77 (3H), 2.86 (1H), 3.44 (1H), 3.55 (2H), 3.69 (1H), 4.46 (IH), 4.67 (IH), 5.01 (1H), 5.05 (IH), 5.46 (1H), 5.70 (1H), 6.09 (1H), 6.69 (2H), 6.99 (1H), 7.04 (1H), 7.16 (1H), 7.32 (1H), 7.77 (1H), 7.92 (1H) ppm.
3o Example EL46 11-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-undecanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-8-hydroxy-5,5,9, I 3-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yloxycarbonyloxymethyl]-2-chloro-phenyl ester Example EL46a 11-(2,S-Dioxo-2,S-dihydro-pyrrol-1-yl)-undecanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-8-(tert-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yloxycarbonyloxymethyl]-2-chloro-phenyl ester Analogously to Example ELl2b, 323 mg (459 ~mol) of the compound prepared according to Example ELl2a are reacted with 790 mg of the compound prepared according to Example L 17. After working-up and purification, 96 mg (88 p.mol, 19°J°) to of the title compound are isolated.
Example EL46 11-(2,S-Dioxo-2,5-dihydro-pyrrol-1-yl)-undecanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-S-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yloxycarbonyloxymethyl]-2-chlor-phenyl ester Analogously to Example EL1, 59 mg (54 wmol) of the compound prepared according to Example EL46a are reacted. After working-up and purification, 27 mg (27.7 p.mol, 51%) of the title compound are isolated.
1H-NMR. (CDCl3): cS = 1.01 (3H), 1.13 (3H), 1.15 (3H), 1.23-2.70 (31H), 1.71 (3H), 2.74 (3H), 2.99 (1H), 3.40 (1H), 3.51 (2H), 3.68 (1H), 4.49 (1H), 4.70 (1H), 5.00 (IH), 5.04 (1H), 5.18 (1H), S.S6 (1H), 5.71 (1H), 5.99 (1H), 6.68 (2H), 6.95 (1H), 7.03 (1H), 7.11 (1H), 7.36 (1H), 7.75 (1H), 7.95 (1H) ppm.
Example EL47 11-(2,5-Dioxo-2,S-dihydro-pyrrol-1-yl)-undecanoic acid 4-(1S,3S,7S,lOR,11S,12S, 16R)-[ 10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-S-yl)-5,9-dioxo-4, I 7-dioxa-bicyclo [ 14.1.OJheptadec-7-yloxycarbonyloxymethyl]-2-chloro-phenyl ester (A) and 11-(2,5-Dioxo-2,S-dihydro-pyrrol-1-yl)-undecanoic acid 4-( 1 R,3 S,7S, I OR, l I S, I 2S,16S)-[ 10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-3o methyl-benzothiazol-S-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-7-yloxycarbonyloxymethyl]-2-chloro-phenyl ester (B) Analogously to Example EL2, 27 mg (27 ~mol) of the compound prepared according to Example EL46 are reacted. After working-up and purification, 14 mg ( 14.1 p,mol, 52%) of the title compound A as well as 5 mg (5.0 ~,mol, 19%) of the title compound B are isolated.
~H-NMR (CDCl3) of A: 8 = 1.02 (3H), 1.13 (3H), 1.15 (3H), 1.19-1.84 (27H), 2.09-2.74 (8H), 2.77 (3H), 2.85 (1H), 3.44 (1H), 3.50 (2H), 3.69 (1H), 4.46 (IH), 4.67 (1H), 5.01 (1H), 5.06 (1H), 5.45 (IH), 5.70 (IH), 6.08 (IH), 6.68 (2H), 6.99 (IH), 7.04 (1H), 7.16 (1H), 7.31 (1H), 7.76 (1H), 7.91 (1H) ppm.
Example EL48 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-butanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-io allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-2-chloro-phenyl ester Example EL48a 4-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-butanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-is allyl-4-(tert-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-2-chloro-phenyl ester Analogously to Example ELl2b, 340 mg (482 ~,mol) of the compound prepared according to Example ELl4a are reacted with 885 mg of the compound prepared 20 according to Example L15. After working-up and purification, 151 mg (152 ~.mol, 32%) of the title compound are isolated.
Example EL48 4-(2,S-Dioxo-2,S-dihydro-pyrrol-1-yl)-butanoic acid 4-(4S,7R,8S,9S,I3Z,I6S)-[7-2S allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothia~ol-S-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-2-chloro-phenyl ester Analogously to Example ELl, 151 mg (152 pmol) of the compound prepared according to Example EL48a are reacted. After working-up and purification, 46 mg (S2 ~mol, 34%) of the title compound are isolated.
30 'H-NMR (CDCl3): ~ = 1.02 (3H), 1.07 (3H), 1.26 (3H), I.71 (3H), I.15-2.44 (13H), 2.51 (2H), 2.65 (2H), 2.84 (3H), 2.91 ( 1 H), 3.55 ( 1 H), 3.68 (2H), 3.99 ( 1 H), 4.92 ( 1 H), 4.98 (1H), 5.06-5.25 (4H), 5.70 (1H), 5.83 (1H), 6.72 (2H), 7.17 (1H), 7.31 (1H), 7.34 (1H), 7.49 (1H), 7.80 (1H), 7.96 (IH) ppm.

Example EL49 4-(2,S-Dioxo-2,S-dihydro-pyrrol-1-yl)-butanoic acid 4-(1S,3S,7S,lOR,IIS,I2S, 16R) [10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-S-yl)-S,9-dioxo 4,17-dioxa-bicyclo[14.1.0]heptadec-11-yloxycarbonyloxymethyl]-2-chloro-phenyl ester (A) and 4-(2,S-Dioxo-2,S-dihydro-pyrrol-1-yl)-butanoic acid 4-(1 R,3 S,7S, I OR,11 S,12S,16S)-[ 10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-S-yl)-S,9-dioxo-4,17-dioxa-bicyclo [ 14.1.OJheptadec-11-yloxycarbonyloxymethyl]-2-chlaro-phenyl ester (B) l0 Analogously to Example EL2, 46 mg (S2 p.mol) of the compound prepared according to Example EL48 are reacted. After working-up and purification, 6 mg (6.7 ~mol, 13%) of the title compound A as well as 1 mg (l.l ~,mol, 2%) of the title compound B
are isolated.
1H-NMR (CDC13) of A: b = 0.97 (3H), 1.04 (3H), 1.24 (3H), 1.30 (3H), 1.14-2.76 1S (2IH), 2.85 (3H), 3.68 (3H), 4.09 (1H), 4.23 (1H), 4.91 (1H), 4.97 (1H), 5.11 (2H), 5.22 (1H), 5.72 (1H), 6.25 (1H), 6.72 (2H), 7.16 (1H), 7.30 (1H), 7.37 (1H), 7.48 (1H), 7.83 ( 1 H), 7.99 ( 1 H) ppm.
Example ELSO
20 6-(2,S-Dioxo-2,S-dihydro-pyrrol-1-yl)-hexanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-4-hydroxy-S,S,9,13-tetramethyl-16-(2-methyl-benzothiazol-S-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-2-chloro-phenyl ester Example ELSOa 2S 6-(2,S-Dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-4-(tert-butyl-dirnetlryl-silanyloxy)-S,S;9,13-tetramethyl-I 6-(2-methyl-benzothiazol-S-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyloxymethylJ-2-chloro-phenyl ester Analogously to Example ELl2b, 340 mg (482 p.mol) of the compound prepared 3o according to Example ELl4a are reacted with 848 mg of the compound prepared according to Example L 16. After working-up and purification, 1 S 8 mg ( 1 S S
p.mol, 32%) of the title compound are isolated.

Example EL50 6-(2,5-Dioxo-2,S-dihydro-pyrrol-1-yl)-hexanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-4-hydroxy-5, 5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2, 6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-2-chloro-phenyl ester Analogously to Example ELl, 158 mg (155 ~mol) of the compound prepared according to Example ELSOa are reacted. After working-up and purification, S8 mg (64 ~.mol, 41%) of the title compound are isolated.
iH NMR (CDCl3): ~ = 1.02 (3H), 1.08 (3H), 1.22 (3H), 1.71 (3H), 0.90-2.45 (17H), 2.51 (2H), 2.61 (2H), 2.83 (3H), 2.88 (1H), 3.55 (3H), 3.97 (1H), 4.92 (1H), 4.98 (1H), io 5.10-5.25 (4H), 5.71 (1H), 5.83 (1H), 6.69 (2H), 7.12 (1H), 7.30 (1H), 7.34 (iH), 7.49 (1H), 7.79 (1H), 7.95 (1H) ppm.
Example ELS I
6-(2,5-Dioxo-2,S-dihydro-pyrrol-1-yl)-hexanoic acid 4-(1S,3S,7S,lOR,11S,12S, 16R)-[10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-S-yl)-S,9-dioxo-4,17-dioxa-bicyclo [ 14.1.0]heptadec-11-yloxycarbonyloxymethyl]-2-chloro-phenyl ester (A) and 6-(2,5-Dioxo-2,S-dihydro-pyrrol-1-yl)-hexanoic acid 4-(1R,3 S,7S,1 OR,11 S,125,16S)-[ 10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[ 14.1.0]heptadec-11-2o yloxycarbonyloxymethyl]-2-chloro-phenyl ester (B) Analogously to Example EL2, 58 mg (64 ~,mol) of the compound prepared according to Example EL50 are reacted. After working-up and purification, 25 mg (27 ~,mol, 42%) of the title compound A as well as 7 mg (7.6 ~.mol, 12%) of the title compound B are isolated.
1H-NMR (CDCl3) of A: 8 = 0.97 (3H), 1.04 (3H), 1.24 (3H), 1.31 (3H), 1.12-2.65 (21H), 2.72 (1H), 2.84 (3H), 3.55 (2H), 3.71 (1H), 4.08 (1H), 4.22 (1H), 4.91 (1H), 4.96 (1H), 5.12 (2H), 5.23 (1H), 5.72 (1H), 6.24 (1H), 6.69 (2H), 7.13 (1H), 7.30 (1H), 7.37 (1H), 7.48 (1H), 7.83 (1H), 7.97 (1H) ppm.
3o Example EL52 11-(2,5-Dioxo-2,5-dihydro-pyrrol-1-y1)-undecanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-2-chloro-phenyl ester Example EL52a 11-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-undecanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-4-(tert-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl)-2-chloro-phenyl ester Analogously to Example ELl2b, 355 mg (476 ~mol) of the compound prepared according to Example ELl4a are reacted with 790 mg of the compound prepared according to Example L 17. After working-up and purification, 122 mg ( 112 ~mol, l0 24%) of the title compound are isolated.
Example EL52 11-(2,5-Dioxo-2,S-dihydro-pyrrol-1-yl)-undecanoic acid 4-(4S,7R,8S,9S,13Z,16S)-[7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-is oxacyclohexadec-13-en-8-yloxycarbonyloxymethyl]-2-chloro-phenyl ester Analogously to Example EL1, 122 mg (112 ~.mol) of the compound prepared according to Example EL52a are reacted. After working-up and purification, 28 mg (29 ~.mol, 26%) of the title compound are isolated.
IH-N1VIR (CDCl3): b = 1.02 (3H), 1.08 (3H), 1.22 (3H), 1.11-2.48 (26H), 1.71 (3H), 20 2.51 (2H), 2.61 (2H), 2.83 (3H), 2.89 (1H), 3.46-3.58 (3H), 3.98 (1H), 4.6I
(2H), 4.92 (1H), 4.98 (1H), 5.11-5.25 (3H), 5.70 (1H), 5.83 (1H), 6.68 (2H), 7.00 (1H), 7.18 (1H), 7.29 (1H), 7.36 (1H), 7.79 (1H), 7.95 (1H) ppm.
Example EL53 25 11-(2,5-Dioxo-2,S-dihydro-pyrrol-1-yl)-undecanoic acid 4-(1S,3S,7S,lOR,11S,12S, 16R)-[ 10-allyl-7-hydroxy-8, 8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo [ 14.1.0]heptadec-11-yloxycarbonyloxymethyl]-2-chloro-phenyl ester (A) and 11-(2,5-Dioxo-2,5-dihydro-pyrrol-1-yl)-undecanoic acid 4-( 1 R,3 S,7S,1 OR,11 S,12S,16S)-[ 10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-30 benzothiazol-S-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-11-yloxycarbonyloxymethyl]-2-chloro-phenyl ester (B) Analogously to Example EL2, 28 mg (29 wmol) of the compound prepared according to Example EL52 are reacted. After working-up and purification, 6.2 mg (6.3 pmol, 22%) of the title compound A as well as 0.3 mg (0.3 ~.mol, 1 %) of the title compound B are isolated.
1H-NMR (CDC13) of A: 8 = 0.97 (3H), 1.04 (3H), 1.23 (3H), 0.82-1.83 (25H), 2.16 (2H), 2.24-2.65 (7H), 2.72 (1H), 2.84 (3H), 3.50 (2H), 3.70 (1H), 4.08 (1H), 4.21 (1H), s 4.92 ( 1 H), 4.97 ( 1 H), 5.11 (2H), 5.22 ( 1 H), 5.72 ( 1 H), 6.25 ( 1 H), 6.67 (2H), 7.12 ( 1 H), 7.30 (1H), 7.37 (1H), 7.49 (1H), 7.83 (1H), 7.98 (1H) ppm.
Example EL54 (4S,7R,8S,9S,13Z,I6S)-Carbonic acid 7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2-1o methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yl ester 4-[4-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-3-vitro-butyrylamino]-benzyl ester Example EL54a (4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-8-(tert-butyl-dimethyl-silanyloxy)-15 5,5,9,13-teixamethyl-I6-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yl ester 4-amino-benzyl ester Analogously to Example ELl2b, 160 mg (227 ~mol) of the compound prepared according to Example ELl2a are reacted with 191 mg (4-amino-3-vitro-phenyl)-methanol. After working-up and purification, 51 mg (61 ~.mol, 27%) of the title 2o compound are isolated.
IH-NMR (CDCl3): ~ = 0.07 (3H), 0.12 (3H), 0.92 (9H), 0.99 (3H), 1.03 (3H), 1.23 (3H), 0.85-1.74 (8H), 1.93 (1H), 2.28 (1H), 2.38 (2H), 2.49 (1H), 2.66 (1H), 2.77 (3H), 2.82 (1H), 2.97 (1H), 3.22 (1H), 3.87 (1H), 4.85-5.03 (4H), 5.22 (1H), 5.42 (1H), 5.74 (1H), 5.89 (1H), 6.10 (2H), 6.68 (1H), 7.19 (1H), 7.32 (1H), 7.73 (1H), 7.90 (1H), 7.98 25 ( 1 H) ppm.
Example EL54b (4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-8-(tert-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-3o en-4-yl ester 4-[4-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-butyrylamino]-3-vitro-benzyl ester 153 mg (837 ~mol) of the compound prepared according to Example L4 are mixed with 1.82 ml thionyl chloride and refluxed for 3.5 hours. The mixture is diluted with toluene and evaporated. A solution of 130 mg (156 ~.mol) of the compound prepared according to Example S4a in 6 ml dichloromethane is added, 75 ~,l pyridine are admixed, and the mixture is stirred at 23°C for 16 hours. It is poured into water, .
extracted several ~ times with dichloromethane, the combined organic extracts are 5 washed with water and dried over sodium sulfate. After filtration and removal of the solvent, the residue is purified by chromatography. 101 mg (101 ~,mol, 6S%) of the title compound are isolated.
Example EL54 10 (4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-8-hydroxy-S,S,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-y1)-2,6-dioxo-oxacyclohexadec-13-en-4-yl ester 4-[4-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-butyrylamino]-3-vitro-benzyl ester Analogously to Example ELI, 101 mg (101 ~mo1) of the compound prepared according to Example EL54a are reacted. After working-up and purification, 62 mg 15 (70 ~.mol, 69%) of the title compound are isolated.
1H-NMR (CDC13): S = 1.01 (3H), 1.14 (6H), 1.39 (2H), 1.64 (2H), 1.71 (3H), 1.80 (2H), 2.07 (2H), 2.23-2.54 (8H), 2.69 (1H), 2.77 (3H), 2.96 (1H), 3.39 (IH), 3.65 (2H), 3.69 (1H), 4.52 (1H), 4.75 (1H), 5.00 (1H), 5.05 (IH), 5.18 (1H), 5.55 (1H), 5.71 (1H), 5.98 (IH), 6.71 (2H), 7.31 (1H), 7.36 (1H), 7.77 (1H), 7.91 (1H), 7.93 (1H), 8.67 (1H), 20 10.28 (1H) ppm.
Example ELSS
( 1 S,3 S,7S,1 OR,1 I S, I 2S,16R)-Carbonic acid 10-allyl-1 I -hydroxy-8, 8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-S,9-dioxo-4,17-dioxa-25 bicyclo[14.1.0]heptadec-7-yl ester 4-[4-(2,5-dioxo-2,5-dihydro-pyrrol-I-yl)-butyrylamino]-3-vitro-benzyl ester (A) and (1R,3S,7S,lOR,I IS,I2S,16S)-Carbonic acid 10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-S-yl)-S,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-7-yl ester 4-[4-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-butyrylamino]-3-vitro-benzyl ester (B) 3o Analogously to Example EL2, 62 mg (70 ~.mol) of the compound prepared according to Example EL54 are reacted. After working-up and purification, 38 mg (42 pmol, 60%) of the title compound A as well as I I mg (12 ~.mol, 17%) of the title compound B are isolated.

1H-NMR (CDCl3) of A: ~ = 1.03 (3H), 1.13 (3H), 1.17 (3H), 1.32 (3H), 1.20-2.s8 (17H), 2.70 (1H), 2.79 (3H), 2.85 (1H), 3.43 (1H), 3.65 (2H), 3.69 (1H), 4.s2 (1H), 4.72 (1H), 5.01 (1H), 5.05 (1H), 5.45 (1H), 5.70 (1H), 6.07 (1H), 6.71 (2H), 7.31 (1H), 7.3s (1H), 7.78 (1H), 7.88 (1H), 7.95 (1H), 8.68 (1H), 10.28 (1H) ppm.
s Example EL56 (4S,7R,8S,9S,13Z,I6S)-Carbonic acid 7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-s-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yl ester 4-[6-(2,5-dioxo-2,s-dihydro-pyrrol-1-yl)-hexanoylamino]-3-nitro-benzyl ester to Example EL56a (4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-8-(tert-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazal-5-yl)-2,6-dioxo-oxacyclohexadec-en-4-yl ester 4-[6-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoylamino]-3-nitro-benzyl is ester Analogously to Example EL54b, s0 mg (60 ~.mol) of the compound prepared according to Example ELS4a are reacted with the compound prepared according to Example LS. After working-up and purification, 58 mg (56 pmol, 94%) of the title compound axe isolated.
Example EL56 (4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yl ester 4-[6-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoylamino]-3-nitro-benzyl ester 2s .Analogously to Example EL1, 82 mg (80 ~,mol) of the compound prepared according to Example ELS6a are reacted. After working-up and purification, 34 mg (37 p.mol, 46%) of the title compound are isolated.
1H-NMR (CDCl3): 8 = 1.01 (3H), 1.14 (6H), 1.70 (3H), 1.31-2.57 (20H), 2.69 (1H), 2.78 (3H), 2.97 (1H), 3.39 (1H), 3.s4 (2H), 3.69 (1H), 4.s1 (1H), 4.74 (1H), 5.00 (1H), 3o S.OS (1H), 5.18 (1H), S.sS (iH), 5.78 (1H), s.98 (1H), 6.69 (2H), 7.31 (1H), 7.36 (1H), 7.76 ( 1 H), 7.92 ( 1 H), 7.93 ( 1 H), 8.71 ( 1 H), 10.32 ( 1 H) ppm.
Example EL57 (1 S,3 S,7S, l OR,11 S, I 2S,16R)-Carbonic acid 10-allyl-11-hydroxy-8,8,12, I

tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-7-yl ester 4-[6-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoylamino]-3-vitro-benzyl ester (A) and (IR,3S,7S,lOR,11S,12S,16S)-Carbonic acid 10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,I7-dioxa-bicyclo[14.1.0]heptadec-7-yl ester 4-[6-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoylamino]-3-vitro-benzyl ester (B) Analogously to Example EL2, 34 mg (37 p,mol) of the compound prepared according to Example EL56 are reacted. After working-up and purification, 19 mg (20.4 p.mol, 55%) of the title compound A as well as 6 mg (6.4 ~mol, 17%) of the title compound B are isolated.
1H-NMR (CDC13) of A: ~ = 1.02 (3H), 1.14 (3H), 1.15 (3H), 1.39 (2H), 1.70 (3H), 1.65 (2H), I.80 (2H), 2.06 (2H), 2.23-2.55 (8H), 2.69 (1H), 2.77 (3H), 2.97 (1H), 3.39 (1H), 3.65 (2H), 3.69 (1H), 4.52 (1H), 4.75 (1H), 5.00 (1H), 5.05 (1H), 5.18 (1H), 5.55 (1 H), 5.71 ( 1 H), 5.97 ( 1 H), 6.71 (2H), 7.31 (1H), 7.36 ( 1 H), 7.76 ( 1 H), 7.91 ( 1 H), 7.93 (1H), 8.68 (1H), 10.28 (1H) ppm.
Example EL58 (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-[I1-(2,5 dioxo-2,5-dihydro-pyrrol-1-yl)-undecanoylamino]-3-vitro-benzyl ester Example EL58a (4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-8-(tert-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-S-yl)-2,6-dioxo-oxacyclohexadec-en-4-yl ester 4-[11-(2,5-dioxo-2,5-dihydro-pyrrol-1-yI)-undecanoylamino]-3-nitro-benzyl ester Analogously to Example EL54b, 130 mg (I56 ~,mol) of the compound prepared according to Example EL54a are reacted with the compound prepared according to 3o Example L6. After working-up and purification, 120 mg (I09 ~.mol, 70%) of the title compound are isolated.
Example EL58 (4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yl ester 4-[11-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-undecanoylamino]-3-vitro-benzyl ester Analogously to Example EL1, 120 mg (109 ~mol) of the compound prepared according to Example EL58a are reacted. After working-up and purification, 89 mg (90 ~,mol, 83%) of the title compound are isolated.
1H-NMR (CDCl3): cS = 1.01 (3H), I.13 (3H), 1.14 (3H), 1.70 (3H), 1.04-2.56 (30H), 2.69 (1H), 2.78 (3H), 2.97 (1H), 3.39 (1H), 3.50 (2H), 3.69 (1H), 4.52 (1H), 4.74 (1H), S.OI (IH), 5.05 (1H), 5.I8 (1H), 5.55 (1H), 5.71 (1H), 5.97 (1H), 6.67 (2H), 7.31 (1H), 7.36 (1H), 7.76 (1H), 7.91 (1H), 7.93 (1H), 8.72 (1H), 10.33 (1H) ppm.
Example EL59 (1 S,3S,7S, l OR,11 S,125,16R)-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-[11-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-undecanoylamino]-3-vitro-benzyl ester (A) and (1 R,3 S,7S, l OR,11 S,125,16S)-Carbonic acid 10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-7-yl ester 4-[11-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-undecanoylamino]-3-vitro-benzyl ester (B) 2o Analogously to Example EL2, 89 mg (90 ~mol) of the compound prepared according to Example EL58 are reacted. After working-up and purification, 45 mg (pmol, %) of the title compound A as well as 15 mg (p.mol, %) of the title compound B are isolated.
rH-NMR (CDC13) of A: 8 = 1.03 (3H), 1.13 (3H), 1.16 (3H), 1.20-1.83 (26H), 2.09-2.57 (8H), 2.72 (1H), 2.79 (3H), 2.86 (1H), 3.44 (1H), 3.50 (2H), 3.69 (1H), 4.51 (IH), 4.72 (1H), 5.01 (1H), 5.05 (1H), 5.45 (1H), 5.71 (1H), 6.08 (1H), 6.68 (2H), 7.32 (1H), 7.35 (1H), 7.78 (IH), 7.88 (1H), 7.96 (1H), 8.73 (1H), 10.33 (1H) ppm.
Example EL60 (4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2-3o methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yI ester 6-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-hexyl ester Example EL60a (4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-8-(tert-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-en-4-yl ester 6-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-hexyl ester Analogously to Example ELl2b, 1.25 g (1.77 mmol) of the compound prepared according to Example ELI2a are reacted with 1.75 g of the compound prepared according to L18. After working-up and purification, 119 mg (138 ~,mol, 8%) of the title compound are isolated.
Example EL60 to (4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-8-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-4-yl ester 6-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-hexyl ester Analogously to Example EL1, 101 mg (117 ~,mol) of the compound prepared according to Example EL60a are reacted. After working-up and purification, 68 mg (91 pmol, 77%) of the title compound are isolated.
1H-NMR (CDCl3): 8 = 1.02 (3H), 1.12-1.87 (19H), 1.70 (3H), 2.23-2.56 (6H), 2.66 ( 1 H), 2.83 (3 H), 2.97 ( I H), 3 .40 (2H), 3 .48 (2H), 3 .68 ( 1 H), 3.75 ( I H), 5.01 ( 1 H), 5.05 (1H), 5.17 (2H), 5.51 (IH), 5.72 (1H), 5.97 (1H), 6.68 (2H), 7.35 (1H), 7.78 (1H), 7.92 ( I H) ppm.
Example EL61 ( 1 S,3 S,7S,1 OR,11 S,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 6-(2,S-dioxo-2,5-dihydro-pyrrol-1-yl)-hexyl ester (A) and ( 1 R,3 S,7S,1 OR,1 I S,125,16S)-Carbonic acid 10-allyl-1 I -hydroxy-8, 8,12,16-tetramethyl-3-(2-methyl-benzothiazol-S-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.OJheptadec-7-yl ester 6-(2,S-dioxo-2,5-dihydro-pyrrol-1-yl)-hexyl ester (B) Analogously to Example EL2, 68 mg (91 p,mol) of the compound prepared according 3o to Example EL60 are reacted. After working-up and purification, 26 mg (34 p.mol, 37%) of the title compound A as well as 10 mg (13 ~mol, 14%) of the title compound B are isolated.

1H-NMR (CDC13) of A: 8 = 1.03 (3H), 1.14 (3H), 1.18 (3H), 1.32 (3H), 1.10-1.85 (15H), 2.11-2.43 (5H), 2.52 (1H), 2.70 (1H), 2.84 (3H), 2.86 (1H), 3.38-3.51 (4H), 3 .69 ( 1 H), 3 . 74 ( 1 H), 5.01 ( 1 H), 5.05 ( 1 H), 5.42 ( 1 H), 5.72 ( 1 H), 6.07 ( 1 H), 6.69 (2H), 7.32 (1H), 7.80 (1H), 7.90 (1H) ppm.

Example EL62 (4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yl ester 4-[4-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-3-vitro-butyrylamino]-benzyl ester Example EL62a (4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-4-(tert-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-en-8-yl ester 4-amino-benzyl ester I5 Analogously to Example ELl2b, 1.73 g (2.46 mmol) of the compound prepared according to Example ELl4a are reacted with 2.06 g (4-amino-3-vitro-phenyl)-methanol. After working-up and purification, 420 mg (502 ~,mol, 20%) of the title compound are isolated.
'H-NMR (CDCl3): 8 = -O.IO (3H), 0.09 (3H), 0.84 (9H), 0.96-1.21 (2H), 1.01 (3H), 1.12 (3H), 1.15 (3H), 1.70 (3H), 1.61-1.85 (4H), 2.11 (1H), 2.29 (2H), 2.54-2.78 (3H), 2.83 (3H), 2.90 ( 1 H), 3.31 (1 H), 3.93 (1 H), 4.86 ( 1 H), 4.96 (1 H), 5.04 (1 H), 5.11 (1 H), 5.25 (2H), 5.55 (1H), 5.72 (1H), 6.14 (2H), 6.82 (1H), 7.35 (1H), 7.43 (1H), 7.79 (1H), 7.91 ( 1 H), 8.18 ( 1 H) ppm.
2s Example EL62b (4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-4-(tent-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-en-8-yl ester 4-[4-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-butyrylamino]-3-vitro-benzyl ester 3o Analogously to Example EL54b, 140 mg (167 ~.mol) of the compound prepared according to Example EL62a are reacted with the compound prepared according to Example L4. After working-up and purification, 150 mg (150 ~.mol, 90%) of the title compound are isolated.

Example EL62 (4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2 methyl-benzothiazol-S-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yl ester 4-[4-(2,5 dioxo-2,S-dihydro-pyrrol-1-yl)-3-vitro-butyrylamino]-benzyl ester Analogously to Example ELI, 145 mg (145 pmol) of the compound prepared according to Example EL62a are reacted. After working-up and purification, 67 mg (76 pmol, 52%) of the title compound are isolated.
~H-NMR (CDCl3): 8 = 1.02 (3H), 1.08 (3H), 1.22 (3H), 1.70 (3H), 1.09-2.12 (8H), ~0 2.27-2.55 (8H), 2.83 (3H), 2.87 (2H), 3.56 (1H), 3.65 (2H), 3.99 (1H), 4.93 (1H), 4.98 (IH), 5.12-5.26 (4H), 5.71 (1H), 5.83 (1H), 6.70 (2H), 7.33 (1H), 7.67 (1H), 7.79 (1H), 7.94 (1H), 8.25 (1H), 8.79 (1H), 10.32 (1H) ppm.
Example EL63 ( I S,3 S,7S, I OR,11 S,125,16R)-Carbonic acid 10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-S-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-11-yl ester 4-[4-(2,S-dioxo-2,S-dihydro-pyrrol-1-yl)-butyrylamino]-3-vitro-benzyl ester (A) and (1R,3S,7S,lOR,11S,12S,16S)-Carbonic acid 10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-S-yl)-5,9-dioxo-4, I 7-dioxa-bicyclo[14.1.0]heptadec-11-yl ester 4-[4-(2,S-dioxo-2,S-dihydro-pyrrol-1-yl)-butyrylamino]-3-vitro-benzyl ester (B) Analogously to Example EL2, 67 mg (76 ~mol) of the compound prepared according to Example EL62 are reacted. After working-up and purification, 37 mg (41 ~.mol, 54%) of the title compound A as well as 12 mg (13 ~mol, 18%) of the title compound B are isolated.
Example EL64 (4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2 methyl-benzothiazol-S-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yl ester 4-[4-(2,S
3o dioxo-2,S-dihydro-pyrrol-1-yl)-3-vitro-hexanoylamino]-benzyl ester Example EL64a (4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-4-(tert-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-en-8-yl ester 4-[4-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)- hexanoylamino]-3-nitro-benzyl ester s Analogously to Example EL54b, 140 mg (167 p,mol) of the compound prepared according to Example EL62a are reacted with the compound prepared according to Example L5. After working-up and purification, 155 mg (150 pmol, 90%) of the title compound are isolated.
1o Example EL64 (4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yl ester 4-[4-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-3-nitro-hexanoylamino]-benzyl ester Analogously to Example EL1, 150 mg (151 p,mol) of the compound prepared according 15 to Example EL64a are reacted. After working-up and purification, 68 mg (74 p,mol, 49%) of the title compound are isolated.
'H-NMR (CDCl3): S = 1.02 (3H), 1.07 (3H), 1.23 (3H), 1.70 (3H), 1.16-2.54 (20H), 2.84 (3H), 2.87 (2H), 3.54 (3H), 3.98 (1H), 4.92 (1H), 4.98 (1H), 5.13-5.26 (4H), 5.71 (1H), 5.83 (1H), 6.68 (2H), 7.33 (1H), 7.67 (1H), 7.79 (1H), 7.94 (1H), 8.26 (1H), 8.82 20 (1H), 10.37 (1H) ppm.58 Example EL65 ( 1 S,3 S, 7 S,10R,11 S,12 S,16R)-Carbonic acid 10-allyl-7-hydroxy-8, 8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo [ 14.1.0]heptadec-11-yl 25 ester 4-[4-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)- hexanoylamino]-3-nitro-benzyl ester (A) and (1R,3S,7S,lOR,11S,12S,16S)-Carbonic acid 10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-11-yl ester 4-[4-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoylamino]-3-nitro-benzyl ester (B) 30 Analogously to Example EL2, 68 mg (74 ~,mol) of the compound prepared according to Example EL64 are reacted. After working-up and purification, 44 mg (47 p,mol, 64%) of the title compound A as well as 3 mg (3 pmol, 4%) of the title compound B
are isolated.

Example EL66 (4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yl ester 4-[4-(2,5-s dioxo-2,5-dihydro-pyrrol-1-yl)-3-vitro-undecanoylamino]-benzyl ester Example EL66a (4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-4-(tert-butyl-dimethyl-silanyloxy)-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-en-8-yl ester 4-[4-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)- undecanoylamino]-3-nitro-benzyl ester Analogously to Example EL54b, 140 mg (167 pmol) of the compound prepared according to Example EL62a are reacted with the compound prepared according to Example L6. After working-up and purification, 165 mg (150 ~,mol, 90%) of the title i5 compound are isolated.
Example EL66 (4S,7R,8S,9S,13Z,16S)-Carbonic acid 7-allyl-4-hydroxy-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-2,6-dioxo-oxacyclohexadec-13-en-8-yl ester 4-[4-(2,5-2o dioxo-2,5-dihydro-pyrrol-1-yl)-3-vitro-undecanoylamino]-benzyl ester Analogously to Example EL1, 145 mg (132 pmol) of the compound prepared according to Example EL66a are reacted. After working-up and purification, 106 mg (108 pmol, 82%) of the title compound are isolated.
rH-NMR (CDC13): b = 1.01 (3H), 1.06 (3H), 1.24 (3H), 1.70 (3H), 1.I4-2.57 (30H), 25 2.82 (3H), 2.89 (2H), 3.50 (2H), 3.55 (1H), 4.01 (1H), 4.92 (1H), 4.99 (1H), 5.11-5.28 (4H), 5.70 (1H), 5.83 (1H), 6.69 (2H), 7.34 (1H), 7.67 (1H), 7.79 (1H), 7.96 (1H), 8.26 ( 1 H), 8. 85 ( 1 H), 10.3 8 ( 1 H) ppm.
Example EL67 30 ( 1 S,3 S,7 S,1 OR,11 S,125,16R)-Carbonic acid 10-allyl-7-hydroxy-8,8, I2, I 6-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[ 14.1.0]heptadec-11-yl ester 4-[4-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)- undecanoylamino]-3-vitro-benzyl ester (A) and ( I R,3 S,7S,1 OR,11 S,125,16S)-Carbonic acid I 0-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-[4-(2,5-dioxo-2,5-dihydro-pyrrol-I-yl)-undecanoylamino]-3-nitro-benzyl ester (B) Analogously to Example EL2, 106 mg (108 ~mol) of the compound prepared according to Example EL66 are reacted. After working-up and purification, 58 mg (58 pmol, 54%) of the title compound A as well as 6 mg (6 ~mol, 6%) of the title compound B are isolated.
1H-NMR (CDC13) of A: ~ = 0.96 (3H), 1.04 (3H), 1.23 (3H), 1.31 (3H), 0.81-1.83 (23H), 2.16 (2H), 2.23-2.66 (6H), 2.71 (1H), 2.85 (3H), 3.5 (2H), 3.72 (1H), 4.08 (1H), l0 4.24 (1H), 4.92 (iH), 4.97 (1H), 5.15 (2H), 5.22 (1H), 5.72 (1H), 6.25 (1H), 6.68 (2H), 7.36 (IH), 7.66 (1H), 7.83 (IH), 7.97 (1H), 8.25 (IH), 8.83 (1H), 10.37 (1H) ppm.

Examples of the Synthesis of Effector-Linker Recognition Units (ELE) Example ELE1 [3-(3-(AP39r)-Sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-propyl]-carbamic acid-10-allyl-11-hydroxy-8, 8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-7-yl ester Example ELE 1 a Reduction of an Antibody Fragment with Terminal Cysteine to A single-strand protein that consists of the variable domains of the heavy and light antibody chains (single-chain Fv, scFv) of the amino acid sequence EVQLLESGGGLVQPGGSLRLSCAASGFTFSSFSMSWVRQAPGKGLEWVSSISG
SSGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKPFPYFDY
WGQGTLVTVSSGDGSSGGSGGASEIVLTQSPGTLSLSPGERATLSCRASQSVSS

YYCQQTGRIPPTFGQGTKVEIKGGGCA, which specifically recognizes the fibronectin domain B (ED-B) and is referred to as AP39, is used for coupling after reduction of the c-terminal cysteine.
For reduction, the solution of 661 ~g of tri(2-carboxyethyl)phosphine-2o hydrochloride in 236 ~1 of PBS is mixed with the solution of 1.54 mg of AP39 in 1.12 ml of PBS, and it is incubated for 1.5 hours at 25°C. Desalination is done with a pre-equilibrated NAP-5 column at a concentration of 450 ~l of AP39r and 50 ~,l of PBS.
After elution with 1 ml of PBS, the reduced antibody fragment AP39r is isolated in a concentration of 0.7 mg/ml.
Example ELE1 ( 1 S,3 S,7S(3RS),1 OR,11 S,125,16R)-[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 22.5 ~.l of a 1.38 mmol solution of effector-linker conjugate A in DMSO, prepared according to Example EL2, is added to 400 ~,l of the solution, prepared according to Example ELE1 a, of the reduced antibody fragment, mixed with 77.5 ~.l of PBS and incubated at 25°C for 1 hour. Desalination is done with a pre-equilibrated NAPS column at a concentration of 500 pl of the reaction solution. After elution with PBS, the solution of the title compound is isolated The dilution factor relative to the antibody fragment is approximately 2.5.
m/z (Calc.): 26203.1 m/z (exp.): 26218 ~ 20 Example ELE2 ( 1 S,3 S,7S(3RS),1 OR,11 S,12S,16R)-[S-(3-(AP39r)-Sulfanyl-2,S-dioxo-pyrrolidin-1-yl)-pentyl]-carbamic acid-10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-S-yl)-S,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-7-yl ester to Analogously to Example ELE1, the antibody fragment that is reduced according to Example ELEla is reacted with effector-linker conjugate A that is prepared according to Example EL4, and the solution of the title compound is isolated.
The dilution factor relative to the antibody fragment is approximately 2.5.
m/z (Calc.): 26231..2 m/z (exp.): 26236 ~ 20 Example ELE3 (1 S,3 S,7S(3RS), l OR,11 S,125,16R)-[ 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-S-yl)-S,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-7-yl ester 2o Analogously to Example ELEl, the antibody fragment that is reduced according to Example ELEla is reacted with effector-linker conjugate A that is prepared according to Example EL6, and the solution of the title compound is isolated.
The dilution factor relative to the antibody fragment is approximately 2.5.
m/z (Calc.): 26301.4 mlz (exp.): 26303 ~ 20 Example ELE4 ( 1 S,3 S,7S,1 OR,11 S(3RS),12S,16R)-[3-(3-(AP39r)-Sulfanyl-2,S-dioxo-pyrrolidin-1-yl)-propyl]-carbamic acid-10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-S-yl)-S,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadec-11-yl ester 3o Analogously to Example ELEl, the antibody fragment that is reduced according to Example ELE1 a is reacted with effector-linker conjugate A that is prepared according to Example ELB, and the solution of the title compound is isolated.
The dilution factor relative to the antibody fragment is approximately 2.5.

m/z (Calc.): 26203.2 m/z (exp.): 26206 ~ 20 Example ELE5 ( 1 S,3 S,7S,1 OR,11 S(3RS),125,16R)-[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 Analogously to Example ELE1, the antibody fragment that is reduced according to Example ELE 1 a is reacted with effector-linker conjugate A that is prepared according to Example EL 10, and the solution of the title compound is to isolated. The dilution factor relative to the antibody fragment is approximately 2.5.
m/z (Calc.): 26231.2 m/z (exp.): 26225 ~ 20 Example ELE6 (1 S,3 S(E),75, l OR,11 S,125,16R)-[3-(3-(AP39r)-Sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-15 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 (A) and (1 S,3 S(E),75, I OR,11 S,125,16R)-[3-(3-(AP39r)-Sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-propyl]-carbamic acid-I 1-[3-(2,5-dioxo-2,5-dihydro-pyrrol-I-yl)-2o propylcarbamoyloxy]-8,8,10,I2,16-pentamethyl-3-[1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-7-yl ester (B) Analogously to Example ELEI, the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate that is prepared according to Example EL11, and the solution of the title compounds is 25 isolated. The dilution factor relative to the antibody fragment is approximately 2.5.
mlz (Calc.): 26347.3 m/z (exp.): 26358 ~ 20 Example ELE7 (1S,3S(E),7S,lOR,11S,12S,16R)-N [1-(~4-[2-(7,11-Dihydroxy-8,8,10,12,16-3o pentamethyl-5,9-dioxo-4,17-dioxa-bicyclo[I4.1.0]heptadec-3-yl)-propenyl]-thiazol-2-ylmethyl)-carbamoyl)-ethyl]-3-(AP39r)-disulfanyl-N methyl-propionamide Analogously to Example ELE1, the antibody fragment that is reduced according to Example ELEIa is reacted with effector-linker conjugate A that is prepared according to Example EL16, and the solution of the title compound is isolated. The dilution factor relative to the antibody fragment is approximately 2.5.
m/z (Calc.): 26173 m/z (exp.): 26174 ~ 20 Example ELEB
( 1 S,3 S(E),75,1 OR,11 S,125,16R)-2-[Methyl-(3-(AP39r)-disulfanyl-propionyl)-amino]-propionic acid-4-[2-(7,11-dihydroxy-8,8,10,12,16-pentamethyl-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-3-yl)-propenyl]-thiazol-2-ylmethyl ester Analogously to Example ELEl, the antibody fragment that is reduced to according to Example ELEla is reacted with effector-linker conjugate A that is prepared according to Example EL17, and the solution of the title compound is isolated. The dilution factor relative to the antibody fragment is approximately 2.5.
m/z (Calc.): 26174 m/z (exp.): 26163 ~ 20 Example ELE9 (1S,3S,7S,lOR,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-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-phenyl ester 2o Analogously to Example ELE1, the antibody fragment that is reduced according to Example ELEIa is reacted with effector-linker conjugate A that is prepared according to Example EL13, and the solution of the title compound is isolated. The dilution factor relative to the antibody fragment is approximately 2.5.
m/z (Calc.): 26238 m/z (exp.): 26224 ~ 20 Example ELE 10 (1S,3S,7S,lOR,11S,12S,16R)-Carbonic acid-10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-11-yl ester 4-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-phenyl ester 3o Analogously to Example ELEl, the antibody fragment that is reduced according to Example ELEla is reacted with effector-linker conjugate A that is prepared according to Example EL15, and the solution of the title compound is isolated. The dilution factor relative to the antibody fragment is approximately 2.5.

m/z (Calc.): 26238 m/z (exp.): 26243 ~ 20 Example ELE 1 I
4-(3-(AP39r)-Sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-butanoic acid 4-(1S,3S,7S,lOR,llS, s 12S,16R)-[IO-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[ 14.1.0]heptadec-7-yloxycarbonyloxymethyl]-2-nitro-phenyl ester Analogously to Example ELEI, the antibody fragment that is reduced according to Example ELEla is reacted with effector-linker conjugate A that is to prepared according to Example EL19, and the solution of the title compound is isolated. The dilution factor relative to the antibody fragment is approximately 2.5.
m/z (Calc.): 26383 m/z (exp.): 26377 ~ 20 Example ELE12 I5 4-(3-(AP39r)-Sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-butanoic acid 4-( 1 S,3 S,7S,1 OR,11 S,125,16R)-[ 10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-11-yloxycarbonyloxymethyl]-2-vitro-phenyl ester Analogously to Example ELEI, the antibody fragment that is reduced 2o according to Example ELEla is reacted with effector-linker conjugate A that is prepared according to Example EL25, and the solution of the title compound is isolated. The dilution factor relative to the antibody fragment is approximately 2.5.
m/z (Calc.): 26383 m/z (exp.): 26381 ~ 20 Example ELE13 6-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-hexanoic acid 4-( 1 S,3 S,7 S,1 OR,11 S,12S, 16R)-[ 10-allyl-11-hydroxy-8, 8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[ I4.1.0]heptadec-7-3o yloxycarbonyloxymethyl]-2-vitro-phenyl ester Analogously to Example ELEI, the antibody fragment that is reduced according to Example ELE I a is reacted with the effector-linker conjugate A that is prepared according to Example EL21, and the solution of the title compound is isolated.
The dilution factor relative to the antibody fragment is approximately 2.5.
m/z (Celt.) : 26411 m/z (exp.): 26384 ~ 30 mlz (Celt.) : 25673 m/z (exp.): 25657 ~ 20 (6-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-hexanoic acid fragment) Example ELE 14 11-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-undecanoic acid 4-(1S,3S,7S,lOR,11S,12S,16R)-[10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-l0 methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-7-yloxycarbonyloxymethyl]-2-nitro-phenyl ester Analogously to Example ELE1, the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL23 and the solution of the title compound is isolated.
The IS dilution factor relative to the antibody fragment is approximately 2.5.
m/z (Celt.) : 26482 m/z (exp.): 26477 ~ 20 mlz (Celt.) : 25744 mlz (exp.): 26752 ~ 20 (11-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-undecanoic acid fragment) 20 Example ELE 15 6-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-hexanoic acid 4-(1S,3S,7S,lOR,11S,12S,16R)-[10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-11-yloxycarbonyloxymethyl]-2-nitro-phenyl ester 25 Analogously to Example ELE1, the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL27 and the solution of the title compound is isolated.
The dilution factor relative to the antibody fragment is approximately 2.5.
m/z (Celt.) : 26411 m/z (exp.): 26398 ~ 20 3o m/z (Celt.) : 25673 mlz (exp.): 25665 ~ 20 (6-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-hexanoic acid fragment) Example ELE16 11-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-undecanoic acid 4-( 1 S,3 S,7S,1 OR,11 S,12S, 16R)-[ 10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo [ 14.1.0]heptadec-11-yloxycarbonyloxymethyl]-2-nitro-phenyl ester Analogously to Example ELE1, the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL29 and the solution of the title compound is isolated.
The dilution factor relative to the antibody fragment is approximately 2.5.
m/z (Calc.) : 26482 m/z (exp.): 26491 ~ 20 to m/z (Calc.) : 25744 m/z (exp.): 25757 ~ 20 (11-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-undecanoic acid fragment) Example ELE 17 4-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-butanoic acid 4-(1S,3S,7S,lOR,11S,12S, 16R)-[10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-7-yloxycarbonyloxymethyl]-phenyl ester Analogously to Example ELE1, the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate A that is prepared 2o according to Example EL31 and the solution of the title compound is isolated. The dilution factor relative to the antibody fragment is approximately 2.5.
m/z (Calc.) : 26338 m/z (exp.): 26304 ~ 30 Example ELE18 6-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-hexanoic acid 4-(1S,3S,7S,lOR,11S,12S, 16R)-[10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo [ 14.1.0]heptadec-7-yloxycarbonyloxymethyl]-phenyl ester Analogously to Example ELE1, the antibody fragment that is reduced according to 3o Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL33 and the solution of the title compound is isolated.
The dilution factor relative to the antibody fragment is approximately 2.5.
m/z (Calc.) : 26366 m/z (exp.): 26347 ~ 30 Example ELE19 11-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-undecanoic acid 4-(1S,3S,7S,lOR,11S,12S, 16R)-[10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-s methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-7-yloxycarbonyloxymethyl]-phenyl ester Analogously to Example ELEl, the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL35 and the solution of the title compound is isolated.
The to dilution factor relative to the antibody fragment is approximately 2.5.
m/z (Celt.) : 26437 m/z (exp.): 26412 ~ 30 Example ELE20 4-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-butanoic acid 4-15 (1 S,3 S,7S, l OR,115,125, 16R)-[ 10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo [ 14.1.0]heptadec-11-yloxycarbonyloxymethyl]-2-vitro-phenyl ester Analogously to Example ELE1, the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate A that is prepared 20 according to Example EL37 and the solution of the title compound is isolated. The dilution factor relative to the antibody fragment is approximately 2.5.
m/z (Celt.) : 26338 mlz (exp.): 26338 ~ 20 Example ELE21 25 6-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-hexanoic acid 4-(1S,3S,7S,lOR,11S,12S, 16R)-[10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[ 14.1.0]heptadec-11-yloxycarbonyloxymethyl]-phenyl ester Analogously to Example ELE1, the antibody fragment that is reduced according to 3o Example ELEIa is reacted with the effector-linker conjugate A that is prepared according to Example EL39 and the solution of the title compound is isolated.
The dilution factor relative to the antibody fragment is approximately 2.5.
mlz (Celt.) : 26366 m/z (exp.): 26384 ~ 30 Example ELE22 11-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-undecanoic acid 4-( 1 S,3 S,7S,1 OR,11 S,12S, 16R)-[ 10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-11-yloxycarbonyloxymethyl]-phenyl ester Analogously to Example ELE1, the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL41 and the solution of the title compound is isolated.
The l0 dilution factor relative to the antibody fragment is approximately 2.5.
m/z (Calc.) : 26437 m/z (exp.): 26421 ~ 30 Example ELE23 4-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-butanoic acid 4-(1S,3S,7S,lOR,11S,12S, 16R)-[10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2 methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-7 yloxycarbonyloxymethyl]-2-chloro-phenyl ester Analogously to Example ELE1, the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate A that is prepared 2o according to Example EL43 and the solution of the title compound is isolated. The dilution factor relative to the antibody fragment is approximately 2.5.
m/z (Calc.) : 26373 mlz (exp.): 26358 ~ 20 m/z (Calc.) : 25645 m/z (exp.): 25627 ~ 20 (4-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-butanoic acid fragment) Example ELE24 6-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-hexanoic acid 4-(1S,3S,7S,lOR,11S,12S, 16R)-[10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5, 9-dioxo-4,17-dioxa-bicyclo [ 14.1.0]heptadec-7-3o yloxycarbonyloxymethyl]-2-chloro-phenyl ester Analogously to Example ELE1, the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL45 and the solution of the title compound is isolated.
The dilution factor relative to the antibody fragment is approximately 2.5.
m/z (Calc.) : 26401 m/z (exp.): 26395 ~ 20 Example ELE25 11-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-undecanoic acid 4-(1S,3S,7S,lOR,11S,12S, 16R)-[10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo [ 14.1.0] heptadec-7-yloxycarbonyloxymethyl]-2-chlor-phenyl ester to Analogously to Example ELE1, the antibody fragment that is reduced according to Example ELEla is reacted with the efFector-linker conjugate A that is prepared according to Example EL47 and the solution of the title compound is isolated.
The dilution factor relative to the antibody fragment is approximately 2.5.
m/z (Calc.) : 26471 m/z (exp.): 26463 ~ 20 Example ELE26 4-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-butanoic acid 4-(1S,3S,7S,lOR,11S,12S, 16R)-[10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-11-2o yloxycarbonyloxymethyl]-2-chloro-phenyl ester Analogously to Example ELE1, the antibody fragment that is reduced according to Example ELEIa is reacted with the effector-linker conjugate A that is prepared according to Example EL49 and the solution of the title compound is isolated.
The dilution factor relative to the antibody fragment is approximately 2.5.
m/z (Calc.) : 26373 m/z (exp.): 26341 ~ 30 Example ELE27 6-(3-(AP39r)-sulfanyl-2,S-dioxo-pyrrolidin-1-yl)-hexanoic acid 4-(1S,3S,7S,lOR,11S,12S, 16R)-[10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-3o benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-11-yloxycarbonyloxymethyl]-2-chlor-phenyl ester Analogously to Example ELE1, the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL51 and the solution of the title compound is isolated.
The dilution factor relative to the antibody fragment is approximately 2.5.
m/z (Calc.) : 26401 m/z (exp.): 26391 ~ 20 s Example ELE28 11-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-undecanoic acid 4-(1 S,3 S,7S,1 OR,115,125, 16R)-[ 10-allyl-7-hydroxy-8, 8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo [ 14.1.0] heptadec-11-yloxycarbonyloxymethyl]-2-chlor-phenyl ester l0 Analogously to Example ELE1, the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL53 and the solution of the title compound is isolated.
The dilution factor relative to the antibody fragment is approximately 2.5.
m/z (Calc.) : 26471 m/z (exp.): 26466 ~ 20 is Example ELE29 ( 1 S,3 S,7S,1 OR,11 S,125,16R)-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-[4-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-2o yl)-butyrylamino]-3-vitro-benzyl ester Analogously to Example ELE1, the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL55 and the solution of the title compound is isolated.
The dilution factor relative to the antibody fragment is approximately 2.5.
25 m/z (Calc.) : 26337 m/z (exp.): ~ 20 Example ELE30 ( 1 S,3 S,7S,1 OR,11 S,125,16R)-Carbonic acid 10-allyl-11-hydroxy-8, 8,12,16-tetramethyl-3-(2-methyl-benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-3o bicyclo[14.1.0]heptadec-7-yl ester 4-[6-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-hexanoylamino]-3-vitro-benzyl ester Analogously to Example ELE1, the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL57 and the solution of the title compound is isolated.
The dilution factor relative to the antibody fragment is approximately 2.5.
m/z (Calc.) : 26365 mlz (exp.): ~ 20 Example ELE31 (1S,3S,7S,lOR,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-[11-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-undecanoylamino]-3-vitro-benzyl ester to Analogously to Example ELE1, the antibody fragment that is reduced according to Example ELEla is reacted with the effector-linker conjugate A that is prepared according to Example EL59 and the solution of the title compound is isolated.
The dilution factor relative to the antibody fragment is approximately 2.5.
mlz (Calc.) : 26436 m/z (exp.): ~ 20 Example ELE32 ( 1 S,3 S,7S,1 OR,11 S,125,16R)-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 6-(3-(AP39r)-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-2o hexyl ester Analogously to Example ELEl, the antibody fragment that is reduced according to Example ELEIa is reacted with the effector-linker conjugate A that is prepared according to Example EL61 and the solution of the title compound is isolated.
The dilution factor relative to the antibody fragment is approximately 2.5.
m/z (Calc.) : 26246 m/z (exp.): ~ 20 Example ELE33 4-(3-(2H8-Ab)x-sulfanyl-2,5-dioxo-pyrrolidin-1-yl)-butanoic acid 4-(1S,3S,7S,lOR,11S,12S, 16R)-[10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3-(2-methyl-3o benzothiazol-5-yl)-5,9-dioxo-4,17-dioxa-bicyclo[14.1.0]heptadec-11-yloxycarbonyloxymethyl]-2-vitro-phenyl ester 100 ~l of a solution of the thionylated antibody prepared according to Example ELE33a (about 3 nmol, about 6 thiol groups) are mixed with 42.3 ~1 of a 1.1 mM

solution of the effector-linker conjugate A prepared according to Example EL25 in PBS, and the mixture is incubated at 23°C for 1 hour. Desalination is performed by using a pre-equilibrated NAPS column with a loading of 150 ~,l of the reaction solution. After elution with PBS, the solution of the title compound is isolated. The loading factor x of antibody 2H8-A in relation to effector-linker is about 1:4 to 1:5.
Example ELE33a Thionylation of a complete immunoglobuline (IgG), e.g., the 2H8 antibody For the introduction of thionyl groups an amine-free solution of the 2H8 antibody in l0 phosphate buffer having a concentration in the range of about 1-10 mg/ml at a pH of 7.2 is mixed with the 10- to 100-fold excess of 2-iminothiolane and is allowed to react for 1 hour at 23 °C. The number of the introduced thiol groups is 1 to about 15 depending on the excess of reagent.

Claims (28)

Claims:
1. Effector conjugate of general formula (I):
in which R1a, R1b, independently of one another, are hydrogen, C1-C10 alkyl, aryl, aralkyl, or together a -(CH2)m group, in which m is 2 to 5, R2a, R2b, independently of one another, are hydrogen, C1-C10 alkyl, aryl, aralkyl, or together a-(CH2)n group, in which n is 2 to 5, or C2-C10 alkenyl, or C2-C10 alkynyl, R3 is hydrogen; C1-C10 alkyl, aryl or aralkyl, and R4a, R4b, independently of one another, are hydrogen, C1-C10 alkyl, aryl, aralkyl, or together a -(CH2)p group, in which p is 2 to 5, R5 is hydrogen, C1-C10 alkyl, aryl, aralkyl, CO2H, CO2alkyl, CH2OH, CH2Oalkyl, CH2Oacyl, CN, CH2NH2, CH2N(alkyl, acyl)1,2, or CH2Hal, Hal is a halogen atom, R6, R7 in each case are hydrogen, or together an additional bond, or together an oxygen atom, or together an NH group, or together an N-alkyl group, or together a CH2 group, and G is an oxygen atom or CH2, D-E is a group H2C-CH2, HC=CH, C.ident.C, CH(OH)-CH(OH), CH(OH)-CH2, CH2-CH(OH), , O-CH2, or, if G represents a CH2 group, D-E
is also CH2-O, W is a group C(=X)R8, or a bicyclic or tricyclic aromatic or heteroaromatic radical, L3 is hydrogen, or, if a radical in W contains a hydroxyl group, forms a group O-L4 with the latter, or, if a radical in W contains an amino group, forms a group NR25-L4 with the latter, R25 is hydrogen or C1-C10 alkyl, X is an oxygen atom, or two OR20 groups, or a C2-C10 alkylenedioxy group that may be straight or branched, or H/OR9, or a CR10R11 group, R8 is hydrogen, C1-C10 alkyl, aryl, aralkyl, halogen or CN, and R9 is hydrogen or a protective group PG X, R10, R11, in each case independently of one another, are hydrogen, C1-C20 alkyl, aryl, aralkyl, or together with a methylene carbon atom form a 5-to 7-membered carbocyclic ring, Z can represent oxygen or H/OR12, R12 can represent hydrogen or a protective group PG Z, A-Y can represent a group O-C(=O), O-CH2, CH2-C(=O), NR21-C(=O) or NR21-SO2, R20 can represent C1-C20 alkyl, R21 can represent a hydrogen atom or C1-C10 alkyl, PG X, PG Y, and PG Z can represent a protective group PG, and L1, L2, and L4, independently of one another, can represent hydrogen, a group C(=O)Cl, a group C(=S)Cl, a group PG Y or a linker of general formula (III) or (IV);
provided that at least one substituent L1, L2 or L4 represents a linker of general formula (III) or (IV);
the linker of general formula (III) has the following structure, in which T can represent oxygen or sulfur, U can represent oxygen, CHR22, CHR22-NR23-C(=O)-, O-C(=O)-CHR22-NR23-C(=O)-, O-C(=O)-CHR22-NR23-C(=S)-, CHR22-NR23-C(=S)- or NR24a, o can represent 0 to 15, V can represent a bond, aryl, a group or a group s can represent 0 to 4, Q can represent a bond, O-C(=O)-NR24c, O-C(=S)-NR24c, R22 can represent hydrogen, C1-C10 alkyl, aryl or aralkyl, R23 can represent hydrogen or C1-C10 alkyl, R24a, R24b, and R24c, independently of one another, can represent hydrogen or C1-C10 alkyl, q can represent 0 to 15, FG1 can represent C1-C10 alkyl-S3 , , or CO2H; and the linker of general formula (IV) has the following structure, in which T can represent oxygen or sulfur, W1, W2 are the same or different and can represent oxygen or NR24a, o can represent 0 to 5, R24a can represent hydrogen or C1-C10 alkyl, R27 can represent halogen, CN, NO2, CO2R28, or OR28, R28 can represent hydrogen, C1-C10 alkyl, aryl or aralkyl, q can represent 0 to 5, U can represent oxygen, CHR22, CHR22-NR23-C(=O)-, CHR22-NR23-C(=S)- or C1-C20 alkyl, R22 can represent hydrogen, C1-C10 alkyl, aryl or aralkyl, R23 can represent hydrogen or C1-C10 alkyl, r can represent 0 to 20, FG1 can represent C1-C10 alkyl-S3, , or CO2H, as a single isomer or a mixture of different isomers and/or as a pharmaceutically acceptable salt thereof.
2. Effector conjugate according to claim 1, wherein:
A-Y represents O-C(=O) or NR21-C(=O), D-E represents an H2C-CH2 group, G represents a CH2 group, Z represents an oxygen atom, R1a, R1b in each case represent C1-C10 alkyl or together a -(CH2)p group with p equal to 2 or 3 or 4, R2a, R2b, independently of one another, represent hydrogen, C1-C10 alkyl, C2-C10 alkenyl, or C2-C10 alkynyl, R3 represents hydrogen, R4a, R4b, independently of one another, represent hydrogen or C1-C10 alkyl;
R5 represents hydrogen, or C1-C4 alkyl or CH2OH or CH2NH2 or CH2N(alkyl, acyl) 1,2 or CH2Hal, R6 and R7 together represent an additional bond or together an NH group, or together an N-alkyl group, or together a CHI group, or together an oxygen atom, W represents a group C(=X)R8 or a 2-methylbenzothiazol-5-yl radical or a 2-methylbenzoxazol-5-yl radical or a quinolin-7-yl radical or a 2-aminomethylbenzothiazol-5-yl radical or a 2-hydroxymethylbenzothiazol-5-yl radical or a 2-aminomethyl-benzoxazol-5-yl radical or a 2-hydroxymethylbenzoxazol-5-yl radical, X represents a CR10R11 group, R8 represents hydrogen or C1-C4 alkyl or a fluorine atom or a chlorine atom or a bromine atom, R10/R11 represent hydrogen/2-methylthiazol-4-yl or hydrogen/2-pyridyl or hydrogen/2-methyloxazol-4-yl or hydrogen/2-aminomethylthiazol-4-yl or hydrogen/2-aminomethyloxazol-4-yl or hydrogen/2-hydroxymethylthiazol-4-yl or hydrogen/2-hydroxymethyloxazol-4-yl.
3. Effector conjugate according to claim 1 or 2, wherein the effector element is selected from the group that consists of:
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[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]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]-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)-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-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]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]hepta-decane-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]hepta-decane-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,3 S (Z),7 S,1 OR,11 S,12 S,16R)-7,11-Dihydroxy-8, 8,10,12,16-pentamethyl-3-[1-fluoro-2-(2-methyl-thiazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]
heptadecane-5,9-dione;
(1 S,3 S(Z),75, 10R,11S,125,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-thiazol-4-yl)-1-fluoro-vinylJ-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [ 14. l .OJheptadecane-5,9-dione;
( 1 S,3 S(Z),75, l OR,11 S,125,16R)-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]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-thia~ol-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;

( 1 S,3 S(Z),75, l OR,11 S,125,16R)-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;
(1 S,3 S(Z),75,1 OR,11 S,125,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-thiazol-4-yl)-1-chloro-vinyl]-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione;
( 1 S,3 S(Z),75,1 OR,11 S,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-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;
( 1 S,3 S(Z),75,1 OR,11 S,125,16R)-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;
( 1 S,3 S (Z),7 S,1 OR,11 S,125,16R)-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]hepta-decane-5,9-dione;
(1 S,3 S(Z),75, l OR,11 S,125,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-1-fluoro-vinyl]-7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]hepta-decane-5,9-dione;

(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[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]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] hepta-decane-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,125,16R)-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-13-ene-2,6-dione;
(1S,3S(E),75,10R,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-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]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]-5,5,7,9,13-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-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]-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-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-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]-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]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-dioxa-bicyclo[14.1.0]hepta-decane-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]hepta-decane-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,165(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-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]-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-fluoro-vinyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione;
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[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-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]-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-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4-yl)-1-fluoro-vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-oxazol-4-yl)-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]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]hepta-decane-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]hepta-decane-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-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]-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-5,5,9,1.3-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]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]hepta-decane-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]hepta-decane-5,9-dione;
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-thiazol-4-yl)-vinyl]-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-Aminomethyl-thiazol-4-yl)-vinyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione;
(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-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]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-pentamethyl-3-[2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione;
(4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[2-(2-pyridyl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione;
(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-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]heptadecane-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]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-hydroxymethyl-benzothiazol-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-hydroxymethyl-benzothiazol-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-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-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-hydroxymethyl-benzothiazol-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-hydroxymethyl-benzothiazol-5-yl)-10-allyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0]heptadecane-5,9-dione;
(1S,3S,7S,10R,11 S,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-inyl-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione;

(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5-yl)-7-prop-2-inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy-7-prop-2-inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;
(1S,3S,7S,10R,11S,12S,16R)-7,11-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-dione;
(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-dione;
(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-dione;
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-but-3-enyl-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5-yl)-7-but-3-enyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy-7-but-3-enyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;
(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-hydroxymethyl-benzothiazol-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-inyl-5,5,9,13-tetramethyl-16-(2-methyl-benzothiazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzothiazol-5-yl)-7-but-3-inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzothiazol-5-yl)-4,8-dihydroxy-7-but-3-inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;
(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-dione;
(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-dione;
(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-dione;
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-(2-methyl-benzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5-yl)-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione;

(1S,3S,7S,10R,11S,12S,16R)-7,11-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-hydroxymethyl-benzoxazol-5-yl)-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione;
(1S,3S,7S,10R,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-hydroxymethyl-benzoxazol-5-yl)-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione;
(1S,3S,7S,10R,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-hydroxymethyl-benzoxazol-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-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]heptadecane-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]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-hydroxymethyl-benzoxazol-5-yl)-10-allyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione;
(1S,3S,7S,10R,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-inyl-5,5,9,13-tetramethyl-16-(2-methyl-benzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5-yl)-7-prop-2-inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy-7-prop-2-inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;

(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-dione;
(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-dione;
(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-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]heptadecane-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]heptadecane-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]heptadecane-5,9-dione;

(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-but-3-inyl-5,5,9,13-tetramethyl-16-(2-methyl-benzoxazol-5-yl)-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-16-(2-hydroxymethyl-benzoxazol-5-yl)-7-but-3-inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;
(4S,7R,8S,9S,13Z,16S)-16-(2-Aminomethyl-benzoxazol-5-yl)-4,8-dihydroxy-7-but-3-inyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-dione;
(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-dione;
(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-dione;
(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-dioxa-bicyclo[14.1.0]heptadecane-5,9-dione, wherein the hydrogen atoms in the above-mentioned effector elements are replaced in the positions indicated in formula (I) by radicals L1-L3.
4. Effector conjugate according to any one of claims 1-3, wherein the linker is selected from the group that consists of the compounds of general formula (III), wherein V represents a bond or an aryl radical, o is zero, and T is an oxygen atom.
5. Effector conjugate according to any one of claims 1-3, wherein the linker is selected from the group that consists of the compounds of general formula (III), wherein V represents a bond or an aryl radical or a group o is 0 to 4, and Q is a bond or a group
6. Effector conjugate according to claim 5, wherein V is a bond or a group Q is a bond or a group o is 0, 2 or 3, s is 1, and T is an oxygen atom.
7. Effector conjugate according to any one of claims 1-3, wherein the linker is selected from the group that consists of compounds of general formula (IV), wherein o is 0 to 4, and q is 0 to 3.
8. Effector conjugate according to claim 7, wherein o is 0, 2 or 3, W1 is oxygen, q is 0, R22 is hydrogen, C1-C3 alkyl or aralkyl, R23 is hydrogen or C1-C3 alkyl, R24a is hydrogen or C1-C3 alkyl, R27 is fluorine, chlorine, CN, NO2, CO2R28 or OR28, R28 is hydrogen or C1-C5 alkyl, and U is oxygen, CHR22, or CHR22-NR23-C(=O)-.
9. Effector recognition unit conjugate of general formula (I), wherein the substituents therein have the meanings that are mentioned in claim 1, but at least one group FG1 is replaced by a group FG2a or FG26, wherein FG2a or FG2b can have the following meanings:

FG2a: -S-S-, FG2b: -CONH-;

and wherein a recognition unit is conjugated via a sulfur atom with the group FG2a or via an amide function with group FG2b; wherein the recognition unit is selected from the group that consists of peptides, soluble receptors, cytokines, lymphokines, aptamers, spiegehners, recombinant proteins, new framework structures, monoclonal antibodies and fragments of monoclonal antibodies;
as a single isomer or a mixture of different isomers and/or as a pharmaceutically acceptable salt thereof.
10. Effector recognition unit conjugate according to claim 9, wherein the conjugate contains more than one recognition unit, and wherein the recognition units are identical.
11. Effector recognition unit conjugate according to claim 9 or 10, wherein the recognition unit is an antibody, or an antigen-binding fragment thereof, which is specific for an antigen that is selected from the group that consists of the antigens that are cited in Table 1, as well as CD19, CD20, CD40, CD22, CD25, CD5, CD52, CD10, CD2, CD7, CD33, CD38, CD40, CD72, CD4, CD21, CD37, CD30, VCAM, CD31, ELAM, endoglin, VEGFRI/II, .alpha.v.beta.3, Tie1/2, TES23 (CD44ex6), phosphatidylserine, PSMA, VEGFR/VEGF complex and ED-B-fibronectin.
12. Link6er of general formula (III1):

in which RG1 is an O=C=N group or an S=C=N group, and o, V, q and FG1 have the meanings that are mentioned in claim 1;
or linker of general formula (III2):

in which RG2 is a Hal-C(=T)-CHR22 group, or a Hal-C(=T)-CHR22-NR23-C(=T) group, or an R26-C(=O)-O-C(=T)-CHR22 group, or an R26-C(=O)-O-C(=T)-CHR22-NR23-C(=T) group, wherein R26 is C1-C10 alkyl, aryl, or aralkyl, and o, V, q and FG1 have the meanings that are mentioned in claim 1;
or linker of general formula (III3):

in which RG3 is an OH group, or an NHR24a group, or a COOH group, and o, V, q and FG1 have the meanings that are mentioned in claim 1;
but with the proviso that the compound 1-(4-amino-phenyl)-pyrrole-2,5-dione is not included.
13. Linker of general formula (IV1):

in which RG1 is an O=C=N group or an S=C=N group, and o, q, r, W2, R27, U and FG1 have the meanings that are mentioned in claim 1;
or linker of general formula (IV2):

in which RG2 is a Hal-C(=T)-CHR22 group, or a Hal-C(=T)-CHR22-NR23-C(=T) group, or an R26-C(=O)-O-C(=T)-CHR22 group, or an R26-C(=O)-O-C(=T)-CHR22-NR23-C(=T) group wherein R26 is C1-C10 alkyl, aryl, or aralkyl and R22, R23, T, o, q, r, W2, R27, U and FG1 have the meanings that are mentioned in claim 1;
or linker of general formula (IV3):

in which RG3 is an OH group or an NHR24a group or a COOH group, and R24, o, q, r, W2, R27, U and FG1 have the meanings that are mentioned in claim 1.
14. Linker according to claim 12, wherein V represents a bond or an aryl radical, o is equal to zero, and T is an oxygen atom.
15. Linker according to claim 12, wherein V represents a bond or an aryl radical or a group o is 0 to 4, and Q is a bond or a group
16. Linker according to claim 15, wherein V is a bond or a group Q is a bond or a group o is 0,2 or 3, s is 1, and T is an oxygen atom.
17. Linker according to claim 13, wherein o is 0 to 4, and q is 0 to 3.
18. Linker according to claim 17, wherein o is 0, 2 or 3, W1 is oxygen, q is 0, R22 is hydrogen, C1-C3 alkyl or aralkyl, R23 is hydrogen or C1-C3 alkyl, R24a is hydrogen or C1-C3 alkyl, R27 is fluorine, chlorine, CN, NO2, CO2R28 or OR28, R28 is hydrogen, or C1-C5 alkyl, and U is oxygen, CHR22, or CHR22-NR23-C(=O)-.
19. Method for the production of effector conjugates according to any one of claims 1-8, wherein a compound of general formula (I), wherein the substituents have the meanings that are mentioned in claim 1, but the condition that at least one substituent L1, L2 or L4 represent a linker of general formula (III) or (IV) need not be met, and at least one substituent L1, L2 or L4 represents hydrogen, a group C(=O)Cl, or a group C(=S)Cl, is reacted with a linker that is selected from the group that consists of a linker of general formula (III1), (III2), (III3), (IV1), (IV2) or (IV3), as described in claims 12 to 18.
20. Method for the production of effector recognition unit conjugates according to one of claims 9 to 11, wherein an effector conjugate according to any one of claims 1-8 is reacted with at least one recognition unit as defined in claims 9 and 11.
21. Use of a compound of general formula (I), wherein the substituents have the meanings that are mentioned in claim 1, but the condition that at least one substituent L1, L2 or L4 represent a linker of general formula (III) or (IV) need not be met, and at least one substituent L1, L2 or L4 represents hydrogen, a group C(=O)Cl, or a group C(=S)Cl, in a method according to claim 19.
22. Use of a compound of general formula (I) for the production of an effector recognition unit conjugate according to claims 9 to 11.
23. Use of a linker of general formula (III1), (III2), (III3), (IV1), (IV2) or (IV3) in a method according to claim 19.
24. Use of a linker of general formula (III1), (III2), (III3), (IV1), (IV2) or (IV3) for the production of an effector recognition unit conjugate according to any one of claims 9 to 11.
25. Use of a recognition unit, as defined in claim 9 or 11, in a method according to claim 20.
26. Effector recognition unit conjugate according to any one of claims 9 to 11 for use as a medicament.
27. Effector recognition unit conjugate according to any one of claims 9 to 11 for use as a medicament for treating diseases that are associated with proliferative processes.
28. Effector recognition unit conjugate according to any one of claims 9 to 11 for use as a medicament for treating a disease that is selected from the group that consists of tumors, inflammatory diseases, neurodegenerative diseases, angiogenesis-associated diseases, multiple sclerosis, Alzheimer's disease, and rheumatoid arthritis.
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DE10305098A DE10305098A1 (en) 2003-02-07 2003-02-07 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
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US45167303P 2003-03-05 2003-03-05
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