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

Abstract

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

Description

The development of understanding regarding the recognition of binding regions, in particular on the field of monoclonal antibodies or their fragments against specific tumor antigens it, selective tumor therapy through targeted release an anti-tumor agent to think at the destination.

Prerequisite for such an approach where a highly active (toxic) active ingredient (effector) high molecular tumor-specific recognition unit such as to an antibody is coupled is a substantial inactivity of the conjugate, its minimum components represent a recognition unit and an effector until this has reached the destination (tumor). When you arrive at the destination, that binds Conjugate on the cell surface and the active ingredient can, if appropriate after previous internalization of the entire complex.

Successful therapy more solid Tumors, especially those with monoclonal antibodies, can be restricted due to inadequate penetration of the antibody into the tumor as well as the heterogeneous distribution of the corresponding tumor-associated antigen in tumor tissue.

These limitations could be circumvented by specifically targeting the tumor vasculature. The growth of tumors below a volume of approximately 2 mm ³ depends on neoangiogenesis. Further tumor growth is based on an intact vascular system that ensures the supply of nutrients and the disposal of waste products. The selective destruction of this system should therefore lead to the death of the tumor. Attacking the tumor vascular system promises a number of advantages over directly attacking the tumor itself. Compared to tumor cells, endothelial cells are more accessible because no tumor tissue has to be penetrated. Damage to a single tumor container should lead to the death of thousands of tumor cells. In order to damage a tumor vessel, there is no need to kill all endothelial cells. The specific attack of endothelial cells in or near tumors minimizes systemic side effects. Endothelial cells are genetically very stable, so the likelihood of developing resistance to the tumor therapeutic is low.

Within the scope of the present invention was now surprisingly a possibility found the chemically very sensitive, highly functionalized Drug class of epothilones and their analogs with a high molecular weight Recognition unit via different linkers to different positions of the active ingredient to tie.

The present invention lies among other things, the task

• 1. Find a method of using highly active ingredients from the structural class of epothilones and epothilone derivatives link suitable linkers,
• 2. to synthesize suitable linkers,
• 3. Develop a method to conjugate these epothilone linkers with recognition units such as monoclonal antibodies or to link their fragments to immunoconjugates, both chemically and also metabolically for a drug development are sufficiently stable and the in terms of their therapeutic breadth, their selectivity of action and / or undesirable toxic side effects and / or their potency the underlying Epothilones or epothilone derivatives are superior.

worin
R^1a, R^1b unabhängig voneinander Wasserstoff, C₁-C₁₀ Alkyl, Aryl, Aralkyl, oder gemeinsam eine -(CH₂)_m-Gruppe sind, worin m 2 bis 5 ist,
R^2a, R^2b unabhängig voneinander Wasserstoff, C₁-C₁₀ Alkyl, Aryl, Aralkyl, oder gemeinsam eine -(CH₂)_n-Gruppe sind, worin n 2 bis 5 ist, oder C₂-C₁₀ Alkenyl, oder C₂-C₁₀ Alkinyl,
R³ Wasserstoff, C₁-C₁₀ Alkyl, Aryl oder Aralkyl, und
R^4a, R^4b unabhängig voneinander Wasserstoff, C₁-C₁₀ Alkyl, Aryl, Aralkyl, oder gemeinsam eine -(CH₂)_p-Gruppe sind, worin p 2 bis 5 ist,
R5 Wasserstoff, C₁-C₁₀ Alkyl, Aryl, Aralkyl, CO₂H, CO₂Alkyl, CH₂OH, CH₂OAlkyl, CH₂OAcyl, CN, CH₂NH₂, CH₂N(Alkyl, Acyl)_1,2, oder CH₂Hal,
Hal ein Halogen-Atom,
R⁶, R⁷ jeweils Wasserstoff, oder gemeinsam eine zusätzliche Bindung, oder gemeinsam ein Sauerstoff-Atom, oder gemeinsam eine NH-Gruppe, oder gemeinsam eine N-Alkyl-Gruppe, oder gemeinsam eine CH₂-Gruppe, und
G ein Sauerstoffatom oder CH₂ sind,
D–E eine Gruppe H₂C-CH₂, HC=CH, C≡C, CH(OH)-CH(OH), CH(OH)-CH₂,
CH2-CH(OH), HC O / -CH, O-CH₂, oder, falls G eine CH₂-Gruppe darstellt, CH₂-O ist,
W eine Gruppe C(=X)R⁸, oder ein bi- or tricyclischer aromatischer oder heteroaromatischer Rest ist,
L³ Wasserstoff ist, oder, falls ein Rest in W eine Hydroxyl-Gruppe enthält, mit dieser eine Gruppe O-L4 bildet, oder, falls ein Rest in W eine Amino-Gruppe enthält, mit dieser eine Gruppe NR²⁵-L⁴ bildet,
R²⁵ Wasserstoff oder C₁-C₁₀ Alkyl ist,
X ein Sauerstoffatom, oder zwei OR²⁰-Gruppen, oder eine C₂-C₁₀ Alkylendioxy Gruppe, die geradkettig oder verzweigt sein darf, oder H/OR⁹, oder eine CR¹⁰R¹¹-Gruppe,
R⁸ Wasserstoff, C₁-C₁₀ Alkyl, Aryl, Aralkyl, Halogen oder CN, und
R⁹ Wasserstoff oder eine Schutzgruppe PG^X sind,
R¹⁰, R¹¹ jeweils unabhängig voneinander Wasserstoff, C₁-C₂₀ Alkyl, Aryl, Aralkyl sind, oder gemeinsam mit einem Methylenkohlenstoffatom einen 5- bis 7-gliedrigen carbocyclischen Ring bilden,
Z Sauerstoff oder H/OR¹²,
R¹² Wasserstoff oder eine Schutzgruppe PG^Z,
A-Y eine Gruppe O-C(=O), O-CH₂, CH₂-C(=O), NR²¹-C(=O) oder NR²¹-SO₂,
R²⁰ C₁-C₂₀ Alkyl,
R²¹ ein Wasserstoffatom oder C₁-C₁₀ Alkyl,
PG^X, PG^Y, PG^Z eine Schutzgruppe PG, und
L¹, L², L⁴ unabhängig voneinander Wasserstoff, eine Gruppe C(=O)Cl, eine Gruppe C(=S)CI, eine Gruppe PGY oder einen Linker der allgemeinen Formel III darstellen können;
mit der Bedingung, dass mindestens ein Substituent L¹, L² oder L⁴ einen Linker der allgemeinen Formel (III) darstellt;
der Linker der allgemeinen Formel (III) folgende Struktur hat,

worin
T Sauerstoff oder Schwefel,
U Sauerstoff, CHR²², CHR²²-NR²³-C(=O)-, CHR²²-NR²³-C(=S)-, O-C(=O)-CHR²²-NR²³-C(=O)-, O-C(=O)-CHR²²-NR²³-C(=S)- oder NR^24a,
o 0 bis 15,
V eine Bindung, Aryl, eine Gruppe

oder eine Gruppe

s 0 bis 4,
Q eine Bindung, O-C(=O)-NR^24c, O-C(=S)-NR^24c,

R²² Wasserstoff, C₁-C₁₀ Alkyl, Aryl oder Aralkyl
R²³ Wasserstoff oder C₁-C₁₀ Alkyl,
R^24a, R^24b, R^24c unabhängig voneinander Wasserstoff oder C₁-C₁₀ Alkyl,
q 0 bis 15,

darstellen können;
als einheitliches Isomer oder eine Mischung unterschiedlicher Isomere und/oder als ein pharmazeutisch akzeptables Salz hiervon.The present invention accordingly comprises effector conjugates of the general formula 1

wherein
R ^1a , R ^1b independently of one another hydrogen, C ₁ -C ₁₀ alkyl, aryl, aralkyl, or together a - (CH ₂ ) _m group are pe, where m is 2 to 5,
R ^2a , R ^2b independently of one another are hydrogen, C ₁ -C ₁₀ alkyl, aryl, aralkyl, or together are a - (CH ₂ ) _n group, in which n is 2 to 5, or C ₂ -C ₁₀ alkenyl, or C ₂ -C ₁₀ alkynyl,
R ^{3 is} hydrogen, C ₁ -C ₁₀ alkyl, aryl or aralkyl, and
R ^4a , R ^4b independently of one another are hydrogen, C ₁ -C ₁₀ alkyl, aryl, aralkyl, or together are a - (CH ₂ ) _p group, in which p is 2 to 5,
R5 is hydrogen, C ₁ -C ₁₀ alkyl, aryl, aralkyl, CO ₂ H, CO ₂ alkyl, CH ₂ OH, CH ₂ O alkyl, CH ₂ O acyl, CN, CH ₂ NH ₂ , CH ₂ N (alkyl, acyl) _{1 , 2} , or CH ₂ Hal,
Hal is a halogen atom,
R ⁶ , R ^{7 are} each hydrogen, or together an additional bond, or together an oxygen atom, or together an NH group, or together an N-alkyl group, or together a CH ₂ group, and
G is an oxygen atom or CH ₂ ,
DE a group H ₂ C-CH ₂ , HC = CH, C≡C, CH (OH) -CH (OH), CH (OH) -CH ₂ ,
CH2-CH (OH), HC O / -CH, O-CH ₂ , or, if G represents a CH ₂ group, CH ₂ -O,
W is a group C (= X) R ⁸ , or a bi- or tricyclic aromatic or heteroaromatic radical,
L ^{3 is} hydrogen, or, if a radical in W contains a hydroxyl group, forms a group O-L4 with it, or, if a radical in W contains an amino group, forms a group NR ²⁵ -L ^{4 with} it .
R ^{25 is} hydrogen or C ₁ -C ₁₀ alkyl,
X represents an oxygen atom, or two OR ²⁰ groups, or a C ₂ -C ₁₀ alkylenedioxy group, which may be straight-chain or branched, or H / OR ⁹ , or a CR ¹⁰ R ¹¹ group,
R ^{8 is} hydrogen, C ₁ -C ₁₀ alkyl, aryl, aralkyl, halogen or CN, and
R ^{9 are} hydrogen or a protective group PG ^X ,
R ¹⁰ , R ^{11 are} each independently hydrogen, C ₁ -C ₂₀ alkyl, aryl, aralkyl, or together with a methylene carbon atom form a 5- to 7-membered carbocyclic ring,
Z oxygen or H / OR ¹² ,
R ^{12 is} hydrogen or a protective group PG ^Z ,
AY is a group OC (= O), O-CH ₂ , CH ₂ -C (= O), NR ²¹ -C (= O) or NR ²¹ -SO ₂ ,
R ²⁰ C ₁ -C ₂₀ alkyl,
R ^{21 is} a hydrogen atom or C ₁ -C ₁₀ alkyl,
PG ^X , PG ^Y , PG ^Z a protective group PG, and
L ¹ , L ² , L ^{4 can} independently represent hydrogen, a group C (= O) Cl, a group C (= S) CI, a group PGY or a linker of the general formula III;
with the condition that at least one substituent L ¹ , L ² or L ^{4 represents} a linker of the general formula (III);
the linker of the general formula (III) has the following structure,

wherein
T oxygen or sulfur,
U oxygen, CHR ²² , CHR ²² -NR ²³ -C (= O) -, CHR ²² -NR ²³ -C (= S) -, OC (= O) -CHR ²² -NR ²³ -C (= O) - , OC (= O) -CHR ²² -NR ²³ -C (= S) - or NR ^24a ,
o 0 to 15,
V a bond, aryl, a group

or a group

s 0 to 4,
Q is a bond, OC (= O) -NR ^24c , OC (= S) -NR ^24c ,

R ^{22 is} hydrogen, C ₁ -C ₁₀ alkyl, aryl or aralkyl
R ^{23 is} hydrogen or C ₁ -C ₁₀ alkyl,
R ^24a , R ^24b , R ^24c independently of one another are hydrogen or C ₁ -C ₁₀ alkyl,
q 0 to 15,

can represent;
as a uniform isomer or a mixture of different isomers and / or as a pharmaceutically acceptable salt thereof.

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

and wherein a recognition unit is conjugated to the group FG2 via a sulfur atom;
wherein the recognition unit can be, for example, a peptide, a soluble receptor, a cytokine, a lymphokine, an aptamer, a Spiegelmer, a recombinant protein, a framework structure, a monoclonal antibody or a fragment of a monoclonal antibody.

According to this invention, the called effector recognition unit conjugates one or more recognition units include; can those associated with a conjugate Detection units can be identical or different. It is preferred that the recognition units of a conjugate are identical.

The conjugates of the invention are preferred for the Treatment of diseases associated with proliferative processes, used. For example, the most varied of therapies are mentioned Tumors, inflammatory therapy and / or neurodegenerative diseases such as multiple sclerosis or Alzheimer's disease, therapy associated with angiogenesis Diseases such as the growth of solid tumors, rheumatoid arthritis or diseases of the fundus.

The epothilones, their precursors and derivatives of the general formula I are prepared by the methods known to the person skilled in the art, for example in DE 19907588 , WO 98/25929, WO 99/58534, WO 99u / 2514, WO 99/67252, WO 99 / 67u253, WO 99/7692, EP 99/4915, WO 00/485, WO 00/1333, WO 00 / u66589 , WO 00/49019, WO 00/49020, WO 00/49021, WO 00/71521, WO 00/37473, WO 00/57874, WO 01/92255, WO 01/81342, WO 01/73103, WO 01/64650 , WO 01/70716, US 6204388, US 6387927, US 6380394, US 02/52028, US 02 / u58286, US 02/62030, WO 02/32844, WO 02/30356, WO 02/32844, WO 02/14323, WO 02/8440 are described.

As alkyl groups R ^{1 a} , R ^1b , R ^2a , R ^2b , R ³ , R ^4a , R ^4b , R ⁵ , R ⁸ , R ¹⁰ , R ¹¹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ^24a , R ^24b , R ^24c , R ²⁵ and R ²⁶ are straight or branched chain alkyl groups with 1-20 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl , Heptyl, hexyl, decyl.

The alkyl groups R ^1a , R ^1b , R ^2a , R ^2b , R ³ , R ^4a , R ^4b , R ⁵ , R ⁸ , R ¹⁰ , R ¹¹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ^24a , R ^24b , R ^24c , R ²⁵ and R ²⁶ can also be perfluorinated or substituted by 1-5 halogen atoms, hydroxy groups, C1-C4 alkoxy groups or C ₆ -C ₁₂ aryl groups (which can be substituted by 1-3 halogen atoms).

Aryl radicals R ^1a , R ^1b , R ^2a , R ^2b , R ³ , R ^4a , R ^4b , R ⁵ , R ⁸ , R ¹⁰ , R ¹¹ , R ²² , R ²⁶ and V are substituted and unsubstituted carbocyclic or heterocyclic radicals with one or more heteroatoms such as phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyriumidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl, benzothiazolyl or benzoxazolyl, which can be mono- or polysubstituted by halogen, OH, O-alkyl, CO ₂ H, CO ₂ alkyl, -NH ₂ , -NO ₂ , -N ₃ , -CN, C ₁ -C ₂₀ alkyl, C ₁ -C ₂₀ acyl or C ₁ -C ₂₀ acyloxy groups, in question. The heteroatoms can be oxidized if the aromatic character is not lost as a result goes, such as the oxidation of a pyridyl to a pyridyl-N-oxide.

The bi- and tricyclic aryl radicals W are substituted and unsubstituted carbocyclic or heterocyclic radicals having one or more heteroatoms, such as naphthyl, anthryl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolyl, isoquinolyl, benzoxaziyl, benzofuranyl, tolokinololoxyloloxyloloxyloloxyloloxyloloxyloloxyloloxyloloxyloloxyloloxyloloxyloloxyloloxyloloxinolyloxynololoxinololoxinololoxinololoxinololoxololoxinololoxololoxinololoxinololoxinololoxinololoxinololoxyloloxinololoxylolinoxyloloxin, , Pyridopyridinyl, benzopyrazolyl, benzotriazolyl, or dihydroindolyl, which can be mono- or polysubstituted by halogen, OH, O-alkyl, CO ₂ H, CO ₂ -alkyl, -NH ₂ , -NO ₂ , -N ₃ , -CN, C ₁ -C ₂₀ alkyl, C ₁ -C ₂₀ acyl or C ₁ -C ₂₀ acyloxy groups, in question. The heteroatoms can be oxidized, provided that the aromatic character is not lost, such as the oxidation of a quinolyl to a quinolyl-N-oxide.

The aralkyl groups in R ^1a , R ^1b , R ^2a , R ^2b , R ³ , R ^4a , R ^4b , R ⁵ , R ⁸ , R ¹⁰ , R ¹¹ , R ²² and R ²⁶ can contain up to 14 carbon atoms in the ring, preferably contain 6 to 10 and in the alkyl chain 1 to 8, preferably 1 to 4 atoms. Examples of suitable aralkyl radicals are benzyl, phenylethyl, naphthylmethyl, naphthylethyl, funlmethyl, thienylethyl or pyridylpropyl. The rings can be mono- or polysubstituted by halogen, OH, O-alkyl, CO ₂ H, CO ₂ alkyl, -NO ₂ , -N ₃ , -CN, C ₁ -C ₂₀ alkyl, C ₁ -C ₂₀ -Acyl or C ₁ -C ₂₀ -acyloxy groups.

Representing the protective groups PG are tris (C ₁ -C ₂₀ alkyl) silyl, bis (C ₁ -C ₂₀ alkyl) arylsilyl, (C ₁ -C ₂₀ alkyl) dianlsilyl, tris (aralkyl) silyl, C ₁ -C ₂₀ alkyl, C ₄ -C ₇ cycloalkyl, which may additionally contain an oxygen atom in the ring, alkyl, C ₇ -C ₂₀ aralkyl, C ₁ -C ₂₀ acyl, aroyl, C ₁ -C ₂₀ alkylsulfonyl as well as arylsulfonyl.

As alkyl, silyl and acyl residues for the Protecting groups PG come in particular those known to the person skilled in the art Leftovers into consideration. Preferred from the corresponding alkyl and silyl ethers easily removable alkyl or silyl radicals, such as the methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, Trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, Tribenzylsilyl, triisopropylsilyl, benzyl, para-nitrobenzyl, para-methoxybenzyl radical and alkylsulfonyl and arylsulfonyl radicals. As acyl residues are e.g. Formyl, acetyl, propionyl, isopropionyl, Trichloromethylcarbonyl, pivalyl, butyryl or benzoyl, with Amino and / or hydroxy groups can be substituted in Question.

PG come as amino protecting groups the radicals known to the person skilled in the art. For example called be the Alloc, Boc, Z, Benzyl, f-Moc, Troc, Stabase or Benzostabase group.

Halogen atoms are suitable Fluorine, chlorine, bromine or iodine.

The acyl groups can have 1 to 20 carbon atoms contain, wherein formyl, acetyl, propionyl, isopropionyl and Pivalyl groups are preferred.

The C ₂ -C ₁₀ -alkylene-α, ω-dioxy group which is possible for X is preferably an ethylene ketal or neopentyl ketal group.

Preferred compounds of the general formula 1 are those in which AY OC (= O) or NR ²¹ -C (= O), DE an H ₂ C-CH ₂ group, G a CH ₂ group, Z an oxygen atom, R ^1a , R ^1b each C ₁ -C ₁₀ alkyl or together a - (CH ₂ ) _p group with p equal to 2 or 3 or 4, R ^2a , R ^2b independently of one another hydrogen, C ₁ -C ₁₀ alkyl, C ₂ - C ₁₀ alkenyl, or C ₂ -C ₁₀ alkynyl, R ³ hydrogen; R ^4a , R ^4b independently of one another are hydrogen or C ₁ -C ₁₀ alkyl; R5 is hydrogen, or C ₁ -C ₄ alkyl or CH ₂ OH or CH2NH ₂ or CH ₂ N (alkyl, acyl) _1,2 or CH ₂ Hal, R ⁶ and R ⁷ together an additional bond or together an NH group or together an N-alkyl group or together a CH2 group or together an oxygen atom, W a group C (= X) R ⁸ or a 2-methylbenzothiazol-5-yl radical or a 2-methylbenzoxazol-5-yl radical or a quinolin-7-yl radical or a 2-aminomethylbenzothiazol-5-yl radical or a 2-hydroxymethylbenzothiazol-5-yl radical or a 2-aminomethylbenzoxazol-5-yl radical or a 2-hydroxymethylbenzoxazol-5- yl radical, X is a CR ¹⁰ R ¹¹ group, R8 is hydrogen or C ₁ -C ₄ alkyl or a fluorine atom or a chlorine atom or a bromine atom, R ¹⁰ / R ^{11 is} hydrogen / 2-methylthiazol-4-yl or hydrogen / 2 -Pyridyl or hydrogen / 2-methyloxazol-4-yl or hydrogen / 2-aminomethylthiazol-4-yl or hydrogen / 2-aminomethyloxazol-4-yl or hydrogen / 2-hydroxymethylthiazol-4-yl or hydrogen / 2-hydroxym represent ethyloxazol-4-yl.

As a linker of the general formula (III) Compounds are preferred in which V is a bond or a Aryl radical and T represent oxygen and o is zero.

For use as recombinant proteins the recognition unit comes, for example, from antibodies derived from antibodies Binding regions, so-called CDRs in question.

Use as framework structures high-molecular structures come as a recognition unit, that are not from antibodies are in question. For example, structures are mentioned fibronectin type 3 and crystalline.

As fragments of monoclonal antibodies Use as a recognition unit may be mentioned, for example, as a single chain Fuv, Fab, F (from)  as well as recombinant multimers.

As preferred recognition units come into consideration, for example, for the detection and / or diagnosis and / or therapy of solid tumors and malignancies Haematopoietic diseases Systems are suitable.

As further preferred recognition units come into consideration those who selectively recognize the disease-specific Vascular system, preferably angiogenesis.

Table 1 lists examples of particularly preferred recognition units for the treatment of solid tumors. TABLE 1

As a particularly preferred recognition unit for the treatment of haematological Tumors are also antibodies or antibody fragments like CD19, CD20, CD40, CD22, CD25, CD5, CD52, CD10, CD2, CD7, CD33, CD38, CD40, CD72, CD4, CD21, CD5, CD37 and CD30 called.

Antibodies or their fragments such as VCAM, CD31, ELAM, Endoglin, VEGFRI / II, α _v β ₃ , Tie1 / 2, TES23 (CD44ex6), phosphatidylserine, PSMA, VEGFR / VEGF- are also particularly preferred recognition units for anti-angiogenic therapy. Called complex or ED-B fibronectin.

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

In a compound of the general formula (1) according to the invention, containing one of the above-mentioned basic bodies, the hydrogen atoms in the above-mentioned basic bodies are replaced at the positions indicated in formula (1) by radicals L ¹ -L ³ , the radicals L ¹ -L ³ have the meanings given above.

worin
RG¹ eine O=C=N-Gruppe oder eine S=C=N-Gruppe sein kann, und o, V, q und
FG¹ die bereits oben genannten Bedeutungen haben,
sowie Linker der allgemeinen Formel III²

worin
RG² eine Hal-C(=T)-CHR²²-Gruppe oder eine Hal-C(=T)-CHR²²-NR²³-C(=T)-Gruppe oder eine R²⁶-C(=O)-O-C(=T)-CHR²²-Gruppe oder eine R²⁶-C(=O)-O-C(=T)-CHR²²-NR²³-C(=T)-Gruppe sein kann, R²⁶ C₁-C₁₀ Alkyl, Aryl, Aralkyl sein kann, und o, V, q, T und FG¹ die bereits oben genannten Bedeutungen haben,
sowie Linker der allgemeinen Formel III³

worin
RG³ eine OH-Gruppe oder eine NHR^24a-Gruppe oder eine COOH-Gruppe sein kann, und o, V, q und FG¹ die bereits oben genannten Bedeutungen haben; jedoch mit der Bedingung, dass die Verbindung 1-(4-Amino-phenyl)-pyrrol-2,5-dion nicht umfasst ist.The invention further relates to linkers of the general formula III ¹

wherein
RG ^{1 can be} an O = C = N group or an S = C = N group, and o, V, q and
FG ^{1 have} the meanings already mentioned,
and linkers of the general formula III ²

wherein
RG ^{2 is} a Hal-C (= T) -CHR ²² group or a Hal-C (= T) -CHR ²² -NR ²³ -C (= T) group or an R ²⁶ -C (= O) -OC (= T) -CHR ²² group or an R ²⁶ -C (= O) -OC (= T) -CHR ²² -NR ²³ -C (= T) group, R ^{26 can be} C ₁ -C ₁₀ alkyl , Aryl, aralkyl, and o, V, q, T and FG ^{1 have} the meanings already mentioned,
and linkers of the general formula III ³

wherein
RG ^{3 can be} an OH group or an NHR ^24a group or a COOH group, and o, V, q and FG ^{1 have} the meanings already mentioned above; however, provided that the compound 1- (4-aminophenyl) pyrrole-2,5-dione is not included.

Linkers of the general formulas III ¹ , III ² or III ³ are particularly preferred according to the invention, where V is a bond or an aryl radical, o is zero and T is an oxygen atom.

The invention further relates to methods
a linker of the general formula III ¹
with a compound of general formula 1, in which the condition that at least one group L ¹ , L ² or L ^{4 is} a linker need not be met, and in which L ¹ and / or L ² and / or L ^{4 has} the meaning of a Have a hydrogen atom and free hydroxyl and / or amino groups that are not required for the reaction are optionally protected,
a linker of the general formula III ²
with a compound of general formula I, in which the condition that at least one group L ¹ , L ² or L ^{4 is} a linker need not be met, and L ¹ and / or L ² and / or L ^{4 has} the meaning of a hydrogen atom have and, if necessary, free hydroxyl and / or amino groups which are not required for the reaction are protected, or
a linker of the general formula III ³
with a compound of general formula 1, in which the condition that at least one group L ¹ , L ² or L ^{4 is} a linker need not be met, and L ¹ and / or L ² and / or L ^{4 has} the meaning of a C. (= O) Hal group or a C (= S) Hal group and free hydroxyl and / or amino groups that are not required for the reaction are optionally protected.

The invention further relates to the use of a compound of general formula 1, where the substituents have the meanings given above, but the condition that at least one substituent ent L ¹ , L ² or L ^{4 represents} a linker of the general formula III, need not be fulfilled, and at least one substituent L ¹ , L ² or L ^{4 is} hydrogen, a group C (= O) Cl, or a group C ( S) represents Cl in a process as described above.

The invention further relates to the use of a compound of the general formula 1, where the substituents have the meanings given above, but the condition that at least one substituent L ¹ , L ² or L ^{4 is} a linker of the general formula III need not be met , and at least one substituent L ¹ , L ² or L ^{4 represents} hydrogen, a group C (= O) Cl, or a group C (S) Cl, for producing an effector-recognition unit conjugate as described above.

The invention further relates to the use of a linker of the general formula III ¹ , III ² or III ³ for the preparation of an effector conjugate, as described above.

The invention further relates to the use of a linker of the general formula III ¹ , III ² or III ³ for the production of an effector-recognition unit conjugate as described above.

The invention further relates to the Use of a recognition unit as described above in one of the methods according to the invention for the preparation of an effector-recognition unit conjugate as above described.

The invention further relates to the effector recognition unit conjugates according to the invention for use as a medicament or for the manufacture of a medicament or an pharmaceutical composition.

Finally, the invention relates to Use of the effector recognition unit conjugates according to the invention for the manufacture of medicines for the treatment of diseases, associated with proliferative processes, such as tumors, inflammatory and / or neurodegenerative diseases, multiple sclerosis, disease Alzheimer's, or for the treatment of angiogenesis-associated Diseases such as tumor growth, rheumatoid arthritis or illnesses of the fundus.

Examples for the synthesis of Linkers (L)

Example L1

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

Example L1a

(S) 2 - [(3-Acetylsulfanyl-propionyl) methylamino] propanoic acid ethyl ester

The solution of 15 g (89.5 mmol) of N-methylalanine ethyl ester hydrochloride in 850 ml of anhydrous tetrahydrofuran, 4.1 is added at 23 ° C. g of an approximately 60% sodium hydride dispersion and after 3 hours with 23.5 g of 3-acetylsulfanylpropanoic acid chloride. You leave React for 2 days, mixed with saturated sodium bicarbonate solution and extracted several times with ethyl acetate. The united organic You wash extracts with saturated Sodium chloride solution, dries over Sodium sulfate and cleans the after filtration and removal of solvent residue obtained by chromatography on fine silica gel. 17.6 are isolated g (67.3 mmol, 75%) of the title compound as a colorless oil.

Example L1b

(S) 2 - [(3-mercapto-propionyl) methylamino] propanoic acid

The solution of 17.6 g (67.3 mmol) the compound shown in Example L1a was added to 150 ml of methanol one at 23 ° C with 44 ml of a 5M sodium hydroxide solution and stirred for 5 hours. By encore a 4N hydrochloric acid a pH of 2 and extracted with dichloromethane. The United organic extracts are washed with saturated Sodium chloride solution and dries over Sodium sulfate. The one obtained after filtration and removal of solvent Residue (13.0 g, max. 67.3 mmol) is reacted further without purification.

Example L1c

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

The solution of 4.53 g (max. 23.7 mmol) of the crude product shown in Example L1 b in 135 ml of diethyl ether esterify at 0 ° C with an ethereal solution of diazomethane. Isolated after removal of solvent 4.59 g (22.4 mmol, 94%) of the title compound as a pale yellow oil, which one implemented without cleaning.

Example L1d

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

To the solution of 21 g of 2-methyldisulfanyl-isoindole-1,3-dione in 420 ml of trichloromethane, the solution of 14 g (68.2 mmol) is added compound shown in Example L1c in 180 ml of trichloromethane and stir 16 Hours at 23 ° C. The mixture is concentrated, taken up in dichloromethane and stirred for 0.5 hours. solid fuel is filtered off, the filtrate is concentrated and the residue purified by chromatography on fine silica gel. 16.2 are isolated g (57.2 mmol, 84%) of the title compound as a colorless oil.

Example L1

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

The solution of 10 g (35.3 mmol) of the compound shown in Example L1d in 20 ml of ethanol is mixed with 1 l of pH 7 phosphate buffer, pork liver esterase and incubated at 27 ° C. for 46 hours. By adding a 4N hydrochloric acid, the pH is adjusted to 1, extracted with dichloromethane, dried over sodium sulfate and, after filtration and removal of the solvent, 8.3 g (30.8 mmol, 87%) of the title compound are isolated as a colorless oil, which is reacted without further purification ,
¹ H-NMR (CDCl ₃ ): δ = 1.43 + 1.51 (3H), 2.55 + 2.63 (3H), 2.87 (2H), 2.88 + 3.00 (3H) , 3.08-3.26 (2H), 4.63 + 5.19 (1H), 7.90 (1H) ppm.

Example L2

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

Example L2a

2 - [(3-Acetylsulfanyl-propionyl) methylamino] acetic acid ethyl ester

7.13 g (46.4 mmol) of N-methylglycine ethyl ester hydrochloride is reacted analogously to Example L1a and isolated 6.9 g (27.9 mmol, 60%) of the title compound as a colorless oil.

Example L2b

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

7.6 g (30.7 mmol) of that according to Example L2a shown connection is set in analogy to example L1 b um and isolated 4.92 g (27.8 mmol, 90%) of the title compound as colorless oil.

Example L2c

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

4.92 g (27.8 mmol) according to the example L2b shown connection is set in analogy to example L1c um and isolated 5.01 g (26.2 mmol, 94%) of the title compound as colorless oil.

Example L2d

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

2.00 g (10.5 mmol) of that from Example L2c shown connection is set in analogy to example L1d um and isolated 2.33 g (8.65 mmol, 82%) of the title compound as colorless oil.

Example L2

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

2.00 g (7.83 mmol) of the compound shown in Example L2d is reacted analogously to Example L1 and 0.64 g (2.51 mmol, 32%) of the title compound is isolated as a colorless oil.
¹ H NMR (CDCl ₃ ): δ = 2.41 + 2.56 (3H), 2.61-3.27 (7H), 3.98 (2H), 4.38 (1H) ppm.

Example L3

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

Example L3a

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

7.73 g (31.7 mmol) of N-methylphenylalanine ethyl ester hydrochloride is reacted in analogy to example L1a and 2.3 g (6.82 mmol, 22%) of the title compound as a colorless oil.

Example L3b

(S) 2 - [(3-mercapto-propionyl) methylamino] -3-phenyl-propanoic acid

1.09 g (3.23 mmol) of that from Example L3a shown connection is set in analogy to example L1 b um and isolated 0.744 g (2.78 mmol, 86%) of the title compound as colorless oil.

Example L3c

(S) 2 - [(3-Mercapto-propionyl) methylamino] -3-phenylpropanoic acid methyl ester

0.74 g (2.77 mmol) of that from Example L3b shown connection is set in analogy to example L1c um and isolated 0.77 g (2.74 mmol, 99%) of the title compound as colorless oil.

Example L3

(S) 2 - [(3-Methyltrisulfanyl-propionyl) methylamino] -3-phenylpropanoic acid methyl ester

0.77 g (2.74 mmol) according to the example L3c shown connection is set in analogy to example L1d um and isolated 0.72 g (2.00 mmol, 73%) of the title compound as colorless oil.

Example L3

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

0.72 g (2.00 mmol) of that from Example L3d shown connection is set in analogy to example L1 um and isolated 0.49 g (1.42 mmol, 71%) of the title compound as colorless oil.

Example L4

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

20.0 g (193.9 mmol) of 4-aminobutyric acid are mixed with 19 g of maleic anhydride, 290 ml of acetic acid and heated in an oil bath at 130 ° C. for 4 hours. The mixture is concentrated azeotropically with repeated addition of toluene, the residue is taken up in dichloromethane and purified by chromatography on fine silica gel. 17.1 g (93.4 mmol, 48%) of the title compound are isolated as a crystalline solid.
¹ H NMR (CDCl ₃ ): δ = 1.93 (2H), 2.38 (2H), 3.60 (2H), 6.71 (2H) ppm.

Example L4a

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

5.0 g (27.3 mmol) of that from Example L4 shown disconnects in 90 ml of tetrahydrofuran, mixed with 8 ml of triethylamine, 6.17 ml of phosphoric acid diphenyl ester azide and moves 1.5 hours at 23 ° C. Subsequently 110 ml of toluene are added and the tetrahydrofuran is distilled and warmed up 2 hours at 70 ° C. The The crude product is purified by chromatography on fine silica gel. 1.77 g (9.82 mmol, 36%) of the title compound are isolated.

Example L5

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

100 g (762 mmol) of 6-aminocaproic acid are reacted analogously to Example L5 and 93.8 g (444 mmol, 58%) of the title compound are isolated as a crystalline solid.
¹ H NMR (CDCl ₃ ): δ = 1.34 (2H), 1.55-1.70 (4H), 2.34 (2H), 3.51 (2H), 6.69 (2H) ppm ,

Example L5a

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

10.0 g (47.3 mmol) of that according to Example L5 shown connection is set in analogy to example L4a um and isolated 3.19 g (15.3 mmol, 32%) of the title compound as colorless oil.

Example L6

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

10 g (49.7 mmol) of 11-aminoundecanoic acid are reacted analogously to Example L5 and 6.29 g (22.4 mmol, 45%) of the title compound are isolated as a crystalline solid.
¹ H NMR (CDCl ₃ ): δ = 1.19-1.36 (12H), 1.51-1.67 (4H), 2.34 (2H), 3.49 (2H), 6.68 (2H) ppm.

Example L6a

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

5.28 g (18.8 mmol) according to the example L6 shown connection is set in analogy to example L4a um and isolated 3.37 g (12.1 mmol, 64%) of the title compound as colorless oil.

Example L7

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

The solution of 21.6 g (200 mmol) of 1,4-phenylenediamine in 200 ml of tetrahydrofuran is mixed with the solution of 19.6 g of maleic anhydride over 1.5 hours and stirred at 23 ° C. for 22 hours. It is filtered, washed with tetrahydrofuran and the filtrate is dried. 37.1 g (197 mmol, 98%) of the title compound are isolated as a crystalline solid.
¹ H NMR (d6-DMSO): δ = 6.28 (1H), 6.48 (1H), 6.53 (2H), 7.30 (2H), 7.50-9.00 (2H) ppm.

Example L8

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

The suspension of 5.0 g (45.8 mmol) of 4-aminophenol, 4.49 g of maleic anhydride and 40 ml of acetic acid is heated under reflux for 3 hours. The mixture is concentrated, residual acetic acid is removed azeotropically by repeated distillation with acetic acid and the residue is purified by chromatography on fine silica gel. 2.83 g (15.0 mmol, 33%) of the title compound are isolated.
¹ H NMR (d6-DMSO): δ = 6.83 (2H), 7.09 (2H), 7.13 (2H), 9.71 (1H) ppm.

Examples for 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 EL1a

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

The solution of 6.0 g (7.93 mmol) (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-4,8-bis (terfbutyl-dimethyl-silanyloxy) -5,5,9, 13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) oxacyclohexadec-13-en-2,6-dione, which was prepared in analogy to the process described in WO 00/66589, in 186 ml of anhydrous dichloromethane 26.4 ml of a 20% strength solution of trifluoroacetic acid in dichloromethane are added at 0 ° C. and the mixture is stirred at 0 ° C. for 6 hours. It is poured into saturated sodium bicarbonate solution, extracted with dichloromethane, the combined organic extracts are washed with water and dried over magnesium sulfate. The residue obtained after filtration and removal of solvent is purified by chromatography on fine silica gel. 3.32 g (5.17 mmol, 65%) of the title compound are isolated as a colorless solid.
1H NMR (CDCl ₃ ): δ = 0.09 (3H), 0.12 (3H), 0.93 (9H), 1.00 (3H), 1.06 (3H), 1.22 (3H ), 1.70 (3H), 1.03-1.77 (5H), 1.95 (1H), 2.31-2.56 (6H), 2.83 (3H), 2.87 (1H ), 3.00 (1H), 3.30 (1H), 3.90 (1H), 4.09 (1H), 4.94-5.03 (2H), 5.20 (1H), 5, 77 (1H), 5.88 (1H), 7.34 (1H), 7.78 (1H), 7.95 (1H) ppm.

Example EL1b

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

50 mg (78 μmol) of that according to Example EL1a shown connection triggers in a mixture of 1.5 ml trichloromethane and 1.5 ml dimethylformamide, mixed with 144 mg of the linker shown in Example L4a, 79 mg copper (I) chloride and heated at 70 ° C for 18 hours. The raw mix is purified by chromatography on thin-layer plates and isolated 51 mg (62 μmol, 80%) of the title compound as a colorless oil.

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

The solution of 41 mg (50 μmol) of the compound shown in Example 1b in a mixture of 0.8 ml of tetrahydrofuran and 0.8 ml of acetonitrile is mixed with 310 μl of hexafluorosilicic acid, 310 μl of hydrogen fluoride-pyridine complex and stirred for 23 hours at 23 ° C. It is poured into a 5% sodium hydroxide solution, extracted with ethyl acetate, the combined organic extracts are washed with a saturated sodium chloride solution and dried over sodium sulfate. The residue obtained after filtration and removal of solvent is purified by chromatography on thin-layer plates and isolated 26 mg (36.7 μmol, 73%) of the title compound as a colorless foam.
¹ H NMR (CDCl ₃ ): δ = 0.99 (3H), 1.14 (3H), 1.17 (3H), 1.20-1.51 (3H), 1.54-1.87 (6H), 1.70 (3H), 2.22 (1H), 2.28-3.02 (9H), 2.83 (3H), 3.31 (1H), 3.45 (1H) , 3.68 (1H), 4.44 + 4.83 (1H), 4.99 (1H), 5.03 (1H), 5.15 (1H), 5.61 (1H), 5.72 (1H), 5.91 (1H), 6.68 (2H), 7.36 (1H), 7.78 (1H), 7.90 (1H) ppm.

Example EL2

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

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

The solution of 44 mg (62.2 μmol) of the compound shown in Example 1 in 2.0 ml of dichloromethane is cooled to -50 ° C. and a total of 1.7 ml of an approx. 0.1 M solution of dimethyldioxirane in acetone. It is poured into a saturated sodium thiosulfate solution, extracted with dichloromethane and the combined organic extracts are dried over sodium sulfate. The residue obtained after filtration and removal of the solvent is purified by chromatography on thin-layer plates and 22.7 mg (31.4 μmol, 50%) of the title compound A and 7.6 mg (10.5 μmol, 17%) of the title compound B are each isolated as colorless foam.
¹ H NMR (CDCl ₃ ) of A: δ = 1.01 (3H), 1.14 (3H), 1.16 (3H), 1.20-1.94 (8H), 1.32 (3H ), 2.11-2.74 (9H), 2.82 (1H), 2.84 (3H), 3.30 (2H), 3.48 (2H), 3.68 (1H), 4, 36 + 4.93 (1H), 4.99 (1H), 5.04 (1H), 5.54 (1H), 5.69 (1H), 6.05 (1H), 6.68 (2H) , 7.32 (1H), 7.80 (1H), 7.88 (1H) ppm.
¹ H NMR (CDCl ₃ ) of B: δ = 1.02 (6H), 1.26 (3H), 1.33 (1H), 1.23-2.27 (12H), 2.54-2 , 78 (4H), 2.82 (3H), 2.91 (1H), 3.13 (1H), 3.40 (2H), 3.66 (1H), 4.11 (1H), 4, 84 (1H), 4.95 (1H), 5.01 (1H), 5.70 (1H), 5.81 + 5.93 (1H), 6.04 + 6.13 (1H), 6, 69 (2H), 7.35 (1H), 7.75 (1H), 7.90 + 7.99 (1H) ppm.

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

Example EL3a

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

50 mg (78 μmol) of that according to Example EL1a shown connection is set in analogy to example EL1b around with the linker prepared according to example L5a and isolated after Purification 39 mg (45.9 μmol, 59%) of the title compound as a colorless oil.

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

84 mg (98.8 μmol) of the compound shown in Example EL3a is reacted analogously to Example EL1 and, after purification, 43 mg (58.4 μmol, 59%) of the title compound is isolated as a colorless foam.
¹ H NMR (CDCl ₃ ): δ = 0.89 (3H), 0.96 (3H), 0.85-1.97 (17H), 1.12 (3H), 2.16-3.01 (10H), 2.82 (3H), 3.44 (1H), 3.65 (1H), 4.41 + 4.53 (1H), 4.98 (1H), 5.03 (1H), 5.15 (1H), 5.60 (1H), 5.71 (1H), 5.90 (1H), 6.68 (2H), 7.35 (1H), 7.77 (1H), 7 , 89 + 7.96 (1H) ppm.

Example EL4

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

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

26 mg (35.3 μmol) of the compound shown in Example EL3 are set in analogy to Example EL2 µm and, after purification, isolated 9.1 mg (12.1 μmol, 34%) of the title compound A and 3.0 mg (4.0 μmol, 11%) of the title compound B in each case as a colorless foam.
¹ H NMR (CDCl ₃ ) of A: δ = 0.83-1.94 (15H), 0.98 (3H), 1.14 (3H), 1.16 (3H), 1.32 (3H ), 2.15-2.82 (8H), 2.84 (3H), 3.44 (2H), 3.51 (1H), 3.66 (1H), 4.46 (1H), 4, 99 (1H), 5.04 (1H), 5.54 (1H), 5.69 (1H), 6.06 (1H), 6.68 (2H), 7.33 (1H), 7.80
(1H), 7.89 (1H) ppm. ¹ H NMR (CDCl ₃ ) of B: δ = 0.78-2.74 (23H), 1.01 (3H), 1.03 (3H), 1.33 (3H), 2.82 (3H ), 2.91 (1H), 3.14 (1H), 3.39 (1H), 3.47 (2H), 3.67 (1H), 4.12 (1H), 4.49 (1H) , 4.92-5.06 (2H), 5.53 + 5.80 (1H), 5.69 (1H), 6.11 (1H), 6.68 (2H), 7.34 (1H) , 7.74 + 7.79 (1H), 7.89 + 8.02 (1H) ppm.

Example EL5

(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 EL5a

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

50 mg (78 μmol) of that according to Example EL1a shown connection is set in analogy to example EL1 b around with the linker prepared according to example L6a and isolated after Purification 56 mg (60.8 μmol, 78%) of the title compound as a colorless oil.

Example EL5

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

20 mg (21.7 μmol) of the compound shown in Example EL5a is reacted analogously to Example EL1 and, after purification, 10 mg (12.4 μmol, 57%) of the title compound is isolated as a colorless foam.
¹ H-NMR (CDCl ₃ ): δ = 0.91-1.87 (22H), 0.97 (3H), 1.13 (3H), 1.17 (3H), 1.70 (3H), 2.18-2.69 (8H), 2.80 (1H), 2.82 (3H), 2.96 (1H), 3.47 (1H), 3.50 (2H), 3.66 ( 1H), 3.97 + 4.36 (1H), 4.98 (1H), 5.04 (1H), 5.16 (1H), 5.61 (1H), 5.72 (1H), 5 , 91 (1H), 6.68 (2H), 7.37 (1H), 7.77 (1H), 7.90 + 7.97 (1H) ppm.

Example EL6

(1S, 3S, 7S, 10R, 11S, 12S, 16R) - [10- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) decyl] carbamic acid 10-allyl-11- hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxabicyclo [14.1.0] heptadec-7-yl ester (A) and

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

18 mg (22 μmol) of the compound shown in Example EL5 is reacted analogously to Example EL2 and, after purification, 9.2 mg (11.2 μmol, 51%) of the title compound A and 3.2 mg (3.9 μmol) are isolated , 18%) of the title compound B in each case as a colorless foam.
¹ H NMR (CDCl ₃ ) of A: δ = 0.98 (3H), 1.14 (3H), 1.16 (3H), 1.32 (3H), 1.03-1.67 (21H ), 1.71-1.94 (3H), 2.18-2.78 (9H), 2.83 (3H), 3.50 (3H), 3.66 (1H), 3.87 + 4 , 43 (1H), 4.98 (1H), 5.04 (1H), 5.53 (1H), 5.69 (1H), 6.07 (1H), 6.68 (2H), 7, 33 (1H), 7.80 (1H), 7.89 + 7.93 (1H) ppm.
¹ H NMR (CDCl ₃ ) of B: δ = 0.80-1.64 (21H), 1.01 (3H), 1.03 (3H), 1.25 (3H), 1.33 (3H ), 1.79-2.25 (5H), 2.34 + 3.14 (1H), 2.52-2.76 (4H), 2.81 (3H), 2.91 (1H), 3 , 40 (1H), 3.51 (2H), 3.67 + 3.82 (1H), 4.13 + 4.26 (1H), 4.46 (1H), 4.94 (1H), 5 , 01 (1H), 5.70 (1H), 5.81 + 5.94 (1H), 6.05 + 6.12 (1H), 6.68 (2H), 7.36 (1H), 7 , 74 (1H), 7.91 + 8.02 (1H) ppm.

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- (tert-butyl-dimethyl-silanyloxy) -8-hydroxy-5,5,9,13-tetramethyl-16- (2-methyl -benzothiazol-5-yl) -oxacyclohexadec-13-ene-2,6-dione

The solution of 5.3 g (7.01 mmol) (4S, 7R, 8S, 9S, 13Z, 16S) -7-allyl-4,8-bis (tert-butyl-dimethyl-silanyloxy) -5,5, 9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -oxacyclohexadec-13-en-2,6-dione, which has been prepared in analogy to the process described in WO 00/66589, in one A mixture of 85 ml of tetrahydrofuran and 85 ml of acetonitrile is mixed with 31.7 ml of hexafluorosilicic acid, cooled to 0 ° C., 8.1 ml of trifluoroacetic acid are added dropwise and the mixture is stirred at 0 ° C. for 20 hours. It is poured into water, neutralized by adding a saturated sodium bicarbonate solution and extracted several times with ethyl acetate. The combined organic extracts are washed with saturated sodium chloride solution, dried over sodium sulfate and the residue obtained after filtration and removal of the solvent is purified by chromatography on fine silica gel. 2.82 g (4.39 mmol, 63%) of the title compound are isolated as a colorless solid.
¹ H NMR (CDCl ₃ ): δ = -0.09 (3H), 0.08 (3H), 0.84 (9H), 1.08 (3H), 1.10 (3H), 1.12 (3H), 1.21-1.86 (5H), 1.70 (3H), 2.15 (1H), 2.29-2.97 (8H), 2.84 (3H), 3.14 (1H), 3.96 (1H), 4.03 (1H), 4.97-5.06 (2H), 5.23 (1H), 5.61 (1H), 5.77 (1H), 7.35 (1H), 7.79 (1H), 7.93 (1H) ppm.

Example EL7b

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

100 mg (156 μmol) of that according to Example EL7a shown connection is set in analogy to example EL1 b around with the linker prepared according to Example L4a and isolated after Cleaning 121 mg (147 μmol, 94%) of the title compound as a colorless oil.

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

46 mg (56 μmol) of the compound shown in Example EL7b is reacted analogously to Example EL1 and, after purification, 17 mg (24 μmol, 43%) of the title compound is isolated as a colorless foam.
¹ N NMR (CDCl ₃ ): δ = 0.99-1.30 (2H), 1.03 (3H), 1.07 (3H), 1.21 (3H), 1.51-1.97 (6H), 1.72 (3H), 2.27-2.61 (6H), 2.83 (3H), 2.88 (1H), 3.09 (1H), 3.14 (2H), 3.51 (1H), 3.58 (2H), 4.04 (1H), 4.96-5.04 (2H), 5.12 (1H), 5.19 (1H), 5.28 ( 1H), 5.75 (1H), 5.86 (1H), 6.66 (2H), 7.35 (1H), 7.78 (1H), 7.96 (1H) ppm.

Example EL8

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

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

29 mg (41 μmol) of the compound shown in Example EL7 is reacted analogously to Example EL2 and, after purification, 18 mg (24.9 μmol, 61%) of the title compound A and 3.0 mg (4.1 μmol, 10 %) of the title compound B in each case as a colorless foam.
¹ H NMR (CDCl ₃ ) of A: δ = 0.98 (3H), 1.05 (3H), 1.24 (3H), 1.26 (3H), 1.12-1.83 (9H ), 2.12-2.46 (4H), 2.59 (2H), 2.76 (1H), 2.84 (3H), 3.14 (2H), 3.59 (3H), 3, 98 (1H), 4.10 (1H), 4.95-5.02 (2H), 5.17 (2H), 5.77 (1H), 6.19 (1H), 6.70 (2H) , 7.38 (1H), 7.82 (1H), 7.97 (1H) ppm.
¹ H NMR (CDCl ₃ ) of B: δ = 0.96 (3H), 1.01 (3H), 1.13-1.86 (11H), 1.28 (3H), 1.32 (1H ), 2.16-2.50 (6H), 2.84 (3H), 3.02 (1H), 3.15 (2H), 3.50 (1H), 3.61 (2H), 3, 88 (1H), 4.19 (1H), 4.96-5.04 (2H), 5.13 (1H), 5.28 (1H), 5.78 (1H), 6.33 (1H) , 6.71 (2H), 7.36 (1H), 7.81 (1H), 7.96 (1H) ppm.

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-tert- butyl-dimethylsilyloxy-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -2,6-dioxo-oxacyclohexadec-13-en-8-yl ester

100 mg (156 μmol) of that according to Example EL7a shown connection is set in analogy to example EL1 b around with the linker prepared according to example L5a and isolated after Purification 56 mg (65.9 μmol, 42%) of the title compound as a colorless oil.

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

56 mg (65.9 μmol) of the compound shown in Example EL7b is reacted analogously to Example EL1 and, after purification, 24.7 mg (33.6 μmol, 51%) of the title compound is isolated as a colorless foam.
¹ H-NMR (CDCl ₃ ): δ = 0.97-1.84 (11H), 1.02 (3H), 1.07 (3H), 1.20 (3H), 1.71 (3H), 1.91 (1H), 2.27-2.57 (6H), 2.84 (3H), 2.88 (1H), 2.95 (1H), 3.16 (2H), 3.51 ( 3H), 4.02 (1H), 4.46 + 4.83 (1H), 4.94-5.03 (2H), 5.15 (1H), 5.20 (1H), 5.74 ( 1H), 5.84 (1H), 6.68 (2H), 7.35 (1H), 7.80 (1H), 7.96 (1H) ppm.

Example EL10

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

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

24.7 mg (33.6 μmol) of the compound shown in Example EL9 is reacted analogously to Example EL2 and, after purification, 16.7 mg (22.2 μmol, 66%) of the title compound A and 2.0 mg ( 2.7 μmol, 8%) of the title compound B in each case as a colorless foam.
¹ H NMR (CDCl ₃ ) of A: δ = 0.98 (3H), 1.04 (3H), 1.10-1.75 (13H), 1.23 (3H), 1.26 (3H ), 2.09-2.62 (6H), 2.75 (1H), 2.84 (3H), 3.15 (2H), 3.51 (2H), 3.57 (1H), 3, 99 (1H), 4.08 (1H), 4.46 + 4.74 (1H), 4.93-5.02 (2H), 5.18 (1H), 5.76 (1H), 6, 18 (1H), 6.68 (2H), 7.38 (1H), 7.82 (1H), 7.97 (1H) ppm.
¹ H NMR (CDCl ₃ ) of B: δ = 0.83-1.85 (13H), 0.95 (3H), 1.01 (3H), 1.27 (3H), 1.32 (3H) ), 2.17-2.49 (6H), 2.84 (3H), 3.03 (1H), 3.17 (2H), 3.48 (1H), 3.53 (2H), 3, 86 (1H), 4.18 (1H), 4.66 (1H), 4.94-5.03 (2H), 5.27 (1H), 5.76 (1H), 6.33 (1H) , 6.69 (2H), 7.35 (1H), 7.81 (1H), 7.96 (1H) ppm.

Example EL11

(1 S, 3S (E), 7S, 10R, 11S, 12S, 16R) - [3- (2,5-Dioxo-2,5-dihydro-pyrrol-1-yl) propyl] carbamic acid 7- [ 3- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -propylcarbamoyloxy] -8,8,10,12,16-pentamethyl-3- [1-methyl-2- (2-methyl -thiazol-4-yl) -vinyl] -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptadec-11-yl ester

10 mg (19.7 μmol) (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1- methyl-2- (2-methyl-thiazol-4-yl) vinyl] -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptadecane is used in analogy to example EL1b with that according to example L4a Linker prepared and isolated after purification 7 mg (8.06 μmol, 41%) of the title compound as a colorless oil.
¹ H-NMR (CDCl ₃ ): δ = 0.88-2.20 (13H), 1.03 (3H), 1.05 (3H), 1.10 (3H), 1.24 (3H), 1.28 (3H), 2.08 (3H), 2.63-2.85 (4H), 2.71 (3H), 2.99-3.25 (3H), 3.41-3.50 (3H), 3.62 (2H), 4.88-5.70 (5H), 6.52 (1H), 6.69 (2H), 6.71 (2H), 7.02 (1H ) ppm.

Analogous to the examples mentioned the following effector conjugates are obtained:

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

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

Example EL13

(1 S, 3S, 7S, 10R, 11S, 12S, 16R) -carbonic acid-10-allyl-11-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) -5,9-dioxo-4,17-dioxa-bicyclo (14.1.0] heptadec-7-yl ester 4- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) phenyl ester

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-1-yl) phenyl ester

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

Example EL15

(1S, 3S, 7S, 10R, 11S, 12S, 16R) -Carbonic-10-allyl-7-hydroxy-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) - 5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptadec-11-yl ester 4- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) phenyl ester

Examples for 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 ELE1a

Reduction of one Antibody fragment with terminal cysteine

A single-stranded protein consisting of the variable domains the heavy and light antibodies Chain (single-chain Fv, scFv) of the amino acid sequence EVQLLESGGGLVQPGGSLRLSCAASGFTFSSFSMSWV RQAPGKGLEVWSSISGSSGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAED TAVyyCAKPFPYFDYWGQGTLVTVSSGDGSSGGSGGASEIVLTQSPGTLSLSP GERATLSCRASQSVSSKGSSGR GTDFTLTISRLEPEDFAVYYCQQTGRIPPTFGQGTKVEIKGGGCA, which specifically the Fibronectin domain B (ED-B) recognizes and is referred to as AP39, after reduction of the c-terminal cysteine used for coupling. For reduction the solution of 661 μg Tri (2-carboxyethyl) phosphine hydrochloride in 236 μl PBS with the solution of 1.54 mg AP39 in 1.12 ml PBS and incubated for 1.5 hours at 25 ° C. Desalinate with a pre-equilibrated NAP5 column with a load of 450 μl AP39r and 50 μl PBS. After elution with 1 ml PBS, the reduced antibody fragment is isolated AP39r in a concentration of 0.7 mg / ml.

Example ELE1

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

To 400 μl of that shown in Example ELE1 a solution of the reduced antibody fragment give 22.5 ul a 1.38 mM solution of the effector-linker conjugate A shown in Example EL2 in DMSO, mixed with 77.5 μl PBS and incubated at 25 ° C for 1 hour. Desalt with a pre-equilibrated NAP5 column a load of 500 μl the reaction solution. After elution with PBS, the solution of the title compound is isolated. The dilution factor based on the antibody fragment is about 2.5.

Example ELE2

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

In analogy to example ELE1 sets the antibody fragment reduced according to example ELE1a with that according to example EL4 shown effector-linker conjugate A and isolates the solution of the Title compound. The dilution factor based on the antibody fragment is about 2.5.

Example ELE3

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

In analogy to example ELE1 sets the antibody fragment reduced according to example ELE1a with that according to example EL6 shown effector-linker conjugate A and isolated the solution of Title compound. The dilution factor based on the antibody fragment is about 2.5.

Example ELE4

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

In analogy to example ELE1 sets the antibody fragment reduced according to example ELE1a with that according to example EL8 shown effector-linker conjugate A and isolated the solution of Title compound. The dilution factor based on the antibody fragment is about 2.5.

Example ELE5

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

In analogy to example ELE1 sets the antibody fragment reduced according to example ELE1a with that according to example EL10 shown effector-linker conjugate A and isolated the solution of Title compound. The dilution factor based on the antibody fragment is about 2.5.

Example ELE6

(1S, 3S (E), 7S, 10R, 11 S, 12S, 16R) - [3- (3- (AP39r) -sulfanyl-2,5-dioxopyrrolidin-1-yl) propyl] carbamic acid - 7- [3- (2,5-dioxo-2,5-dihydr o-pyrrol-1-yl) -propylcarbamoyloxy] -8,8,10,12,16-pentamethyl-3- [1-methyl-2- (2-methyl-thiazol-4-yl) -vinyl] -5, 9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptadec-1l-yl ester (A) and

(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) - [3- (3- (AP39r) -sulfanyl-2,5-dioxo-pyrrolidin-1-yl) -propyl] -carbamic acid-11 - [3- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -propylcarbamoyloxy] -8,8,10,12,16-pentamethyl-3- [1-methyl-2- (2 methyl-thiazol-4-yl) -vinyl] -5,9-dioxo-4,17-dioxa-bicyclo [14.1.0] heptadec-7-yl ester (B)

In analogy to example ELE1 sets the antibody fragment reduced according to example ELE1a with that according to example EL11 shown effector-linker conjugate and isolated the solution of Title compounds. The dilution factor based on the antibody fragment is about 2.5.

Claims (19)

Effector conjugate of the general formula (I):

wherein R ^1a , R ^1b independently of one another are hydrogen, C ₁ -C ₁₀ alkyl, aryl, aralkyl, or together are a - (CH ₂ ) _m group, wherein m is 2 to 5, R ^2a , R ^2b independently of one another are hydrogen, C ₁ -C ₁₀ alkyl, aryl, aralkyl, or together are a - (CH ₂ ) _n group, in which n is 2 to 5, or C ₂ -C ₁₀ alkenyl, or C ₂ -C ₁₀ alkynyl, R ^{3 is} hydrogen , C ₁ -C ₁₀ alkyl, aryl or aralkyl, and R ^4a , R ^4b independently of one another are hydrogen, C ₁ -C ₁₀ alkyl, aryl, aralkyl, or together are a - (CH ₂ ) _p group, in which p 2 to 5 is, R5 is hydrogen, C ₁ -C ₁₀ alkyl, aryl, aralkyl, CO ₂ H, CO ₂ alkyl, CH ₂ OH, CH ₂ O alkyl, CH ₂ O acyl, CN, CH ₂ NH ₂ , CH ₂ N (alkyl, Acyl) _1,2 , or CH ₂ Hal, Hal is a halogen atom, R ⁶ , R ^{7 are} each hydrogen, or together an additional bond, or together an oxygen atom, or together an NH group, or together an N - Alkyl group, or together a CH ₂ group, and G is an oxygen atom or CH ₂ , D-E is a group e H ₂ C-CH ₂ , HC = CH, C≡C, CH (OH) -CH (OH), CH (OH) -CH ₂ , CH ₂ CH ((OH), HC O / -CH, O- CH ₂ , O-CH ₂ or, if G represents a CH ₂ group, is CH ₂ -O, W is a group C (= X) R ⁸ , or a bi- or tricyclic aromatic or heteroaromatic radical, L ^{3 is} hydrogen or, if a radical in W contains a hydroxyl group, forms an OL ⁴ group with it, or, if a radical in W contains an amino group, forms a group NR ²⁵ -L ^{4 with} it, R ^{25 forms} hydrogen or C ₁ -C ₁₀ alkyl, X is an oxygen atom, or two OR ²⁰ groups, or a C ₂ -C ₁₀ alkylenedioxy group, which may be straight-chain or branched, or H / OR ⁹ , or a CR ¹⁰ R ¹¹ -Group, R8 are hydrogen, C ₁ -C ₁₀ alkyl, aryl, aralkyl, halogen or CN, and R ^{9 are} hydrogen or a protective group PG ^X , R ¹⁰ , R ^{11 are} each independently hydrogen, C ₁ -C ₂₀ alkyl, aryl , Aralkyl, or together with a methylene carbon atom a 5- to 7-membered carbocyclic ring bil den, Z oxygen or H / OR ¹² , R ¹² hydrogen or a protective group PG ^Z , AY is a group OC (= O), O-CH ₂ , CH2-C (= O), NR ²¹ -C (= O) or NR ²¹ -SO ₂ , R ²⁰ C ₁ -C ₂₀ alkyl, R ^{21 is} a hydrogen atom or C ₁ -C ₂₀ alkyl, PG ^X , PG ^Y , PG ^Z a protective group PG, and L ¹ , L ² , L ⁴ independently of one another hydrogen, a group C (= O) Cl, a group C (= S) Cl , can represent a group PG ^Y or a linker of the general formula (III); with the condition that at least one substituent L ¹ , L ² or L ^{4 represents} a linker of the general formula (III); the linker of the general formula (III) has the following structure,

where T is oxygen or sulfur, U is oxygen, CHR ²² , CHR ²² -NR ²³ -C (= O) -, OC (= O) -CHR ²² -NR ²³ -C (= O) -, OC (= O) - CHR ²² -NR ²³ -C (= S) -, CHR ²² -NR ²³ -C (= S) - or NR ^24a , o 0 to 15, V a bond, aryl, a group

or a group

s 0 to 4, Q is a bond, OC (= O) -NR ^24c , OC (= S) -NR ^24c ,

R ²² hydrogen, C ₁ -C ₁₀ alkyl, aryl or aralkyl R ²³ hydrogen or C ₁ -C ₁₀ alkyl, R ^24a , R ^24b , R ^24c independently of one another hydrogen or C ₁ -C ₁₀ alkyl, q 0 to 15, FG ¹ C ₁ -C ₁₀ alkyl S ₃ - or

can represent; as a uniform isomer or a mixture of different isomers and / or as a pharmaceutically acceptable salt thereof. Effector conjugate according to claim 1, wherein: AY OC (= O) or NR ²¹ -C (= O), DE is an H ₂ C-CH ₂ group, G is a CH2 group, Z is an oxygen atom, R ^1a , R ^1b each C ₁ -C ₁₀ alkyl or together a - (CH ₂ ) _p group with p equal to 2 or 3 or 4, R ^2a , R ^2b independently of one another hydrogen, C ₁ -C ₁₀ Alkyl, C ₂ -C ₁₀ alkenyl, or C ₂ -C ₁₀ alkynyl, R ³ hydrogen; R ^4a , R ^4b independently of one another are hydrogen or C ₁ -C ₁₀ alkyl; R ^{5 is} hydrogen, or C ₁ -C ₄ alkyl or CH ₂ OH or CH ₂ NH ₂ or CH ₂ N (alkyl, acyl) _1,2 or CH ₂ Hal, R6 and R7 together form an additional bond or together form an NH group or together an N-alkyl group or together a CH2 group, or together an oxygen atom, W a group C (= X) R ⁸ or a 2-methylbenzothiazol-5-yl radical or a 2-methylbenzoxazol-5-yl Radical or a quinolin-7-yl radical or a 2-aminomethylbenzothiazol-5-yl radical or a 2-hydroxymethylbenzothiazol-5-yl radical or a 2-aminomethylbenzoxazol-5-yl radical or a 2- Hydroxymethylbenzoxazol-5-yl radical, X a CR ¹⁰ R ¹¹ group R ⁸ hydrogen or C ₁ -C ₄ alkyl or a fluorine atom or a chlorine atom or a bromine atom, R ¹⁰ / R ¹¹ hydrogen / 2-methylthiazol-4-yl or hydrogen / 2-pyridyl or hydrogen / 2-methyloxazol-4-yl or hydrogen / 2-aminomethylthiazol-4-yl or hydrogen / 2-aminomethyloxazol-4-yl or hydrogen / 2-hydroxymethylthiazol-4-yl or hydrogen / 2 -hydro represent xymethyloxazol-4-yl. The effector conjugate according to claim 1 or 2, wherein the effector base is selected from the group consisting of: (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-5,5,7 , 9,13-pentamethyl-16- (1-methyl-2- (2-methylthiazol-4-yl) vinyl] oxacyclohexadec-13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (e)) - 4,8-dihydroxy-16- [2- (2-hydroxymethyl-thiazol-4-yl) -1-methyl-vinyl] -5,5,7,9,13- pentamethyl-oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 16- [2- (2-aminomethylthiazol-4-yl) -1- methylvinyl] -4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R ) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-methyl-2- (2-methyl-thiazol-4-yl) -vinyl] -4.17-dioxa bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- [2- (2-hydroxymethylthiazole-4 -yl) -1-methyl-vinyl] -8,8,10,12,16-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (E) , 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-thiazol-4-yl) -1-methyl-vinyl] -7,11-dihydroxy-8,8,10,12, 16-pentamet hyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-methyl-2- (2-methyl -thiazol-4-yl) -vinyl] -oxacyclohexadec-13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-16- [2- (2-hydroxymethyl-thiazol-4-yl) -1-methyl-vinyl] -7-ethyl -5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 16- [2- (2-Aminomethyl-thiazol-4-yl) -1-methyl vinyl] -4,8-dihydroxy-7-ethyl-5 , 5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-methyl-2- (2 methyl-thiazol-4-yl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- [2- (2-hydroxymethyl-thiazol-4-yl) -1-methyl-vinyl] -10-ethyl -8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-thiazol-4-yl) -1-methyl-vinyl] -7,11-dihydroxy-10 ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-fluoro-2- (2-methyl-thiazol -4-yl) -vinyl] -oxacyclohexadec-13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-16- [2- (2-hydroxymethyl-thiazol-4-yl) -1-fluoro-vinyl] -5,5 , 7,9,13--pentamethyl-oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 16- [2- (2-Aminomethyl-thiazol-4-yl) -1-fluorovinyl] -4,8-dihydroxy-5,5,7 , 9,13-pentamethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-fluoro-2- (2-methyl -thiazol-4-yl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- [2- (2-hydroxymethyl-thiazol-4-yl) -1-fluoro-vinyl] -8,8 , 10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-thiazol-4-yl) -1-fluorovinyl] -7,11-dihydroxy-8,8 , 10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-chloro-2- (2-methyl-thiazol -4-yl) -vinyl] -oxacyclohexadec-13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-16- [2- (2-hydroxymethyl-thiazol-4-yl) -1-chloro-vinyl] -5,5 , 7,9,13- penta methyl-oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 16- [2- (2-Aminomethyl-thiazol-4-yl) -1-chloro vinyl] -4,8-dihydroxy-5,5,7 , 9,13-pentamethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-chloro-2- (2-methyl -thiazol-4-yl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- [2- (2-hydroxymethyl-thiazol-4-yl) -1-chloro-vinyl] -8,8 , 10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-thiazol-4-yl) -1-chloro vinyl] -7,11-dihydroxy-8,8 , 10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-fluoro-2- (2-methyl -thiazol-4-yl) -vinyl] -oxacyclohexadec-13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-16- [2- (2-hydroxymethyl-thiazol-4-yl) -1-fluoro-vinyl] -7-ethyl -5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 16- [2- (2-Aminomethyl-thiazol-4-yl) -1-fluorovinyl] -4,8-dihydroxy-7-ethyl-5 , 5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-fluoro-2- (2 methyl-thiazol-4-yl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- [2- (2-hydroxymethyl-thiazol-4-yl) -1-fluoro-vinyl] -10-ethyl -8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-thiazol-4-yl) -1-fluorovinyl] -7,11-dihydroxy-10-ethyl -8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-chloro-2- (2-methyl -thiazol-4-yl) -vinyl] -oxacyclohexadec-13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-16- [2- (2-hydroxymethyl-thiazol-4-yl) -1-chloro-vinyl] -7-ethyl -5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 16- [2- (2-Aminomethyl-thiazol-4-yl) -1-chloro vinyl] -4,8-dihydroxy-7-ethyl-5 , 5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-ethyl-8,8, 12,16-tetramethyl-3- [1-chloro-2- (2 methyl-thiazol-4-yl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- [2- (2-hydroxymethyl-thiazol-4-yl) -1-chloro-vinyl] -10-ethyl -8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-thiazol-4-yl) -1-chloro vinyl] -7,11-dihydroxy-10-ethyl -8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-methyl-2- (2-pyridyl) - vinyl] -oxacyclohexadec-13-ene-2,6-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-methyl-2- (2-pyridyl ) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-methyl-2- (2-pyridyl ) vinyl] -oxacyclohexadec-l3-en-2,6-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-methyl-2- (2 pyridyl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-fluoro-2- (2-pyridyl) - vinyl] -oxacyclohexadec-13-ene-2,6-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-fluoro-2- (2-pyridyl ) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-chloro-2- (2-pyridyl) - vinyl] -oxacyclohexadec-13-ene-2,6-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-chloro-2- (2-pyridyl ) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-fluoro-2- (2-pyridyl ) -vinyl] -oxacyclohexadec-13-ene-2,6-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-fluoro-2- (2 pyridyl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-L6 [1-chloro-2- (2-pyridyl ) -vinyl] -oxacyclohexadec-13-ene-2,6-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- (1-chloro-2- (2 -pyridyl) -vinyl] -4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy- 5,5,7,9,13-pentamethyl-16- [1-methyl-2- (2-methyl-oxazol-4-yl) vinyl] oxacyclohexadec-13-ene-2,6-dione; (4S , 7R, 8S, 9S, 13Z, 16S (e)) - 4,8-dihydroxy-16- [2- (2-hydroxymethyl-oxazol-4-yl) -1-methyl-vinyl] -5,5,7 , pen-9.13 tamethyl-oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 16- [2- (2-Aminomethyl-oxazol-4-yl) -1-methyl vinyl] -4,8-dihydroxy-5,5,7 , 9,13-pentamethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-methyl-2- (2-methyl oxazole-4-yl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- [2- (2-hydroxymethyl-oxazol-4-yl) -1-methyl-vinyl] -8,8 , 10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (E), 7S, 10R, 11 S, 12S, 16R) -3- [2- (2-aminomethyl-oxazol-4-yl) -1-methyl-vinyl] -7,11-dihydroxy- 8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-methyl-2- (2-methyl oxazole-4-yl) -vinyl] -oxacyclohexadec-13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-16- [2- (2-hydroxymethyl-oxazol-4-yl) -1-methyl-vinyl] -7-ethyl -5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 16- [2- (2-Aminomethyl-oxazol-4-yl) -1-methyl vinyl] -4,8-dihydroxy-7-ethyl-5 , 5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-methyl-2- (2 methyl-oxazol-4-yl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2- (2-hydroxymethyl-oxazol-4-yl) -1-methyl-vinyl] -10-ethyl -8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-aminomethyl-oxazol-4-yl) -1-methyl-vinyl] -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [ 14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [ 1-fluoro-2- (2-methyl-oxazol-4-yl) vinyl] oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-16- [2- (2-hydroxymethyl-oxazol-4-yl) -1-fluoro-vinyl] -5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2, 6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 16- [2- (2-aminomethyl-oxazol-4-yl) -1-fluorovinyl] -4,8-dihydroxy-5 , 5,7,9,13-pentamethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8, 8,10,12,16-pentamethyl-3- [1-fluoro-2- (2-methyl-oxazol-4-yl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecane-5, 9-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2- (2-hydroxymethyloxazo l-4-yl) -1-fluoro-vinyl] -8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-oxazol-4-yl) -1-fluorovinyl] -7,11-dihydroxy-8,8 , 10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-chloro-2- (2-methyl-oxazol -4-yl) -vinyl] -oxacyclohexadec-13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-16- [2- (2-hydroxymethyl-oxazol-4-yl) -1-chloro-vinyl] -5,5 , 7,9,13--pentamethyl-oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 16- [2- (2-Aminomethyl-oxazol-4-yl) -1-chloro vinyl] -4,8-dihydroxy-5,5,7 , 9,13-pentamethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-chloro-2- (2-methyl oxazole-4-yl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- [2- (2-hydroxymethyl-oxazol-4-yl) -1-chloro-vinyl] -8,8 , 10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-oxazol-4-yl) -1-chloro vinyl] -7,11-dihydroxy-8,8 , 10,12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-fluoro-2- (2-methyl oxazole-4-yl) -vinyl] -oxacyclohexadec-13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-16- [2- (2-hydroxymethyl-oxazol-4-yl) -1-fluoro-vinyl] -7-ethyl -5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 16- [2- (2-Aminomethyl-oxazol-4-yl) -1-fluorovinyl] -4,8-dihydroxy-7-ethyl-5 , 5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-fluoro-2- (2 methyl-oxazol-4-yl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- [2- (2-hydroxymethyl-oxazol-4-yl) -1-fluoro-vinyl] -10-ethyl -8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-oxazol-4-yl) -1-fluorovinyl] -7,11-dihydroxy-10-ethyl -8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [1-chloro-2- (2-methyl oxazole-4-yl) -vinyl] -oxacyclohexadec-13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 4,8-dihydroxy-16- [2- (2-hydroxymethyl-oxazol-4-yl) -1-chloro-vinyl] -7-ethyl -5,5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (Z)) - 16- [2- (2-Aminomethyl-oxazol-4-yl) -1-chloro vinyl] -4,8-dihydroxy-7-ethyl-5 , 5,9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [1-chloro-2- (2 methyl-oxazol-4-yl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- [2- (2-hydroxymethyl-oxazol-4-yl) -1-chloro-vinyl] -10-ethyl -8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (Z), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-oxazol-4-yl) -1-chloro vinyl] -7,11-dihydroxy-10-ethyl -8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [2- (2-methyl-thiazol-4-yl ) -vinyl] -oxacyclohexadec-13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-16- [2- (2-hydroxymethyl-thiazol-4-yl) -vinyl] -5,5,7,9 , 13-pentamethyl-oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 16- [2- (2-Aminomethyl-thiazol-4-yl) -vinyl] -4,8-dihydroxy-5,5,7,9 , 13-pentamethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8; 10,12,16-pentamethyl-3- [2- (2-methyl-thiazol-4 -yl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- [2- (2-hydroxymethyl-thiazol-4-yl) -vinyl] -8,8,10,12 , 16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-thiazol-4-yl) -vinyl] -7,11-dihydroxy-8,8,10 , 12,16-pentamethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [2- (2-methyl-thiazol-4 yl) vinyl] -oxacyclohexadec-l3-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-16- [2- (2-hydroxymethyl-thiazol-4-yl) -vinyl] -7-ethyl-5,5 , 9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 16- [2- (2-Aminomethyl-thiazol-4-yl) -vinyl] -4,8-dihydroxy-7-ethyl-5,5 , 9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [2- (2-methyl-thiazol -4-yl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- [2- (2-hydroxymethyl-thiazol-4-yl) -vinyl] -10-ethyl-8,8 , 12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -3- [2- (2-Aminomethyl-thiazol-4-yl) -vinyl] -7,11-dihydroxy-10-ethyl-8 , 8,12,16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [2- (2-pyridyl) -vinyl] -oxacyclohexadec -13-ene-2,6-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-8,8,10,12,16-penta methyl-3- [2- (2-pyridyl) -vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- [2- (2-pyridyl) -vinyl] -oxacyclohexadec-13-ene-2,6-dione; (1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- [2- (2-pyridyl) - vinyl] -4.17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16- (2-methyl-benzothiazol-5-yl) -oxacyclohexadec-13 en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -5,5,7,9,13-pentamethyl-oxacyclohexadec-13- en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-Aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13- en-2,6-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- (2-methyl-benzothiazol-5-yl) -4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethylbenzothiazol-5-yl) -8,8,10,12,16-pentamethyl-4,17- dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -oxacyclohexadec- 13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec- 13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-Aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec- 13-ene-2,6-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) - 4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethylbenzothiazol-5-yl) -10-ethyl-8,8,12,16-tetramethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl- 4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-7-propyl-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -oxacyclohexadec- 13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -7-propyl-5,5,9,13-tetramethyl-oxacyclohexadec- 13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-Aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-propyl-5,5,9,13-tetramethyl-oxacyclohexadec- 13-ene-2,6-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-propyl-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) - 4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethylbenzothiazol-5-yl) -10-propyl-8,8,12,16-tetramethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-propyl-8,8,12,16-tetramethyl- 4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-7-butyl-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -oxacyclohexadec- 13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -7-butyl-5,5,9,13-tetramethyl-oxacyclohexadec- l3-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-Aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-butyl-5,5,9,13-tetramethyl-oxacyclohexadec- 13-ene-2,6-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-butyl-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) - 4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethylbenzothiazol-5-yl) -10-butyl-8,8,12,16-tetramethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-butyl-8,8; 12,16-tetramethyl- 4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-7-allyl-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl) -oxacyclohexadec- 13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -7-allyl-5,5,9,13-tetramethyl-oxacyclohexadec- 13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-Aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-allyl-5,5,9,13-tetramethyl-oxacyclohexadec- 13-ene-2,6-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-allyl-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5-yl) - 4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethylbenzothiazol-5-yl) -10-allyl-8,8,12,16-tetramethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-allyl-8,8,12,16-tetramethyl- 4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-7-prop-2-ynyl-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl ) -oxacyclohexadec-13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -7-prop-2-ynyl-5,5,9,13- tetramethyl-oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-Aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-prop-2-ynyl-5,5,9,13- tetramethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-prop-2-ynyl-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5 -yl) -4.17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethylbenzothiazol-5-yl) -10-prop-2-ynyl-8,8,12,16- tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-prop-2-ynyl-8,8,12, 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-7-but-3-enyl-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl ) -oxacyclohexadec-13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -7-but-3-enyl-5,5,9,13- tetramethyl-oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-Aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-but-3-enyl-5,5,9,13- tetrameth yl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-but-3-enyl-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5 -yl) -4.17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethylbenzothiazol-5-yl) -10-but-3-enyl-8,8,12,16- tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-but-3-enyl-8,8,12, 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-7-but-3-ynyl-5,5,9,13-tetramethyl-16- (2-methyl-benzothiazol-5-yl ) -oxacyclohexadec-13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-16- (2-hydroxymethyl-benzothiazol-5-yl) -7-but-3-ynyl-5,5,9,13- tetramethyl-oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-Aminomethyl-benzothiazol-5-yl) -4,8-dihydroxy-7-but-3-ynyl-5,5,9,13- tetramethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-but-3-ynyl-8,8,12,16-tetramethyl-3- (2-methyl-benzothiazol-5 -yl) -4.17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethylbenzothiazol-5-yl) -10-but-3-ynyl-8,8,12,16- tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 12S, 16R) -3- (2-Aminomethyl-benzothiazol-5-yl) -7,11-dihydroxy-10-but-3-ynyl-8,8,12,16-tetramethyl-4,17- dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16- (2-methyl-benzoxazol-5-yl) -oxacyclohexadec-13 en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -5,5,7,9,13-pentamethyl-oxacyclohexadec-13- en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-Aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13- en-2,6-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- (2-methyl-benzoxazol-5-yl) -4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethylbenzoxazol-5-yl) -8, 8,10,12,16-pentamethyl-4,17- dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16- (2-methyl-benzoxazol-5-yl) -oxacyclohexadec- 13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec- 13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-Aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec- 13-ene-2,6-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-ethyl-8,8,12,16-tetramethyl-3- (2-methyl-benzoxazol-5-yl) - 4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethylbenzoxazol-5-yl) -10-ethyl-8,8,12,16-tetramethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-ethyl-8,8,12,16-tetramethyl- 4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-7-propyl-5,5,9,13-tetramethyl-16- (2-methyl-benzoxazol-5-yl) -oxacyclohexadec- 13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-propyl-5,5,9,13-tetramethyl-oxacyclohexadec- 13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-Aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-propyl-5,5,9,13-tetramethyl-oxacyclohexadec- 13-ene-2,6-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-propyl-8,8,12,16-tetramethyl-3- (2-methyl-benzoxazol-5-yl) - 4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethylbenzoxazol-5-yl) -10-propyl-8,8,12,16-tetramethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-propyl-8,8,12,16-tetramethyl- 4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-7-butyl-5,5,9,13-tetramethyl-16- (2-methyl-benzoxazol-5-yl) -oxacyclohexadec- 13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-butyl-5,5,9,13-tetramethyl-oxacyclohexadec- 13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-Aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-butyl-5,5,9,13-tetramethyl-oxa cyclohexadec-13-ene-2,6-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-butyl-8,8,12,16-tetramethyl-3- (2-methyl-benzoxazol-5-yl) - 4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethylbenzoxazol-5-yl) -10-butyl-8,8,12,16-tetramethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-butyl-8,8,12,16-tetramethyl- 4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-7-allyl-5,5,9,13-tetramethyl-16- (2-methyl-benzoxazol-5-yl) -oxacyclohexadec- 13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-allyl-5,5,9,13-tetramethyl-oxacyclohexadec- 13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-Aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-allyl-5,5,9,13-tetramethyl-oxacyclohexadec- 13-ene-2,6-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-allyl-8,8,12,16-tetramethyl-3- (2-methyl-benzoxazol-5-yl) - 4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethylbenzoxazol-5-yl) -10-allyl-8,8,12,16-tetramethyl-4, 17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-allyl-8,8,12,16-tetramethyl- 4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-7-prop-2-ynyl-5,5,9,13-tetramethyl-16- (2-methyl-benzoxazol-5-yl ) -oxacyclohexadec-13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-prop-2-ynyl-5,5,9,13- tetramethyl-oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-Aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-prop-2-ynyl-5,5,9,13- tetramethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-prop-2-ynyl-8,8,12,16-tetramethyl-3- (2-methyl-benzoxazol-5 -yl) -4.17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethylbenzoxazol-5-yl) -10-prop-2-ynyl-8,8,12,16- tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -3- (2-Aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-prop-2-ynyl-8,8,12, 16-tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-7-but-3-enyl-5,5,9,13-tetramethyl-16- (2-methyl-benzoxazol-5-yl ) -oxacyclohexadec-13-ene-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-Dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-but-3-enyl-5,5,9,13- tetramethyl-oxacyclohexadec-I3-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-Aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-but-3-enyl-5,5,9,13- tetramethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-10-but-3-enyl-8,8,12,16-tetramethyl-3- (2-methyl-benzoxazol-5 -yl) -4.17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-Dihydroxy-3- (2-hydroxymethylbenzoxazol-5-yl) -10-but-3-enyl-8,8,12,16- tetramethyl-4,17-dioxa-bicyclo [14.1.0] heptadecane-5,9-dione; (1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -3- (2-aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10-but-3-enyl-8,8, 12,16-tetramethyl-4,17-dioxabicyclo (14.1.0] heptadecane-5,9-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -4,8-dihydroxy-7-but- 3-inyl-5,5,9,13-tetramethyl-16- (2-methyl-benzoxazol-5-yl) -oxacyclohexadec-13-en-2,6-dione; (4S, 7R, 8S, 9S, 13Z , 16S) -4,8-dihydroxy-16- (2-hydroxymethyl-benzoxazol-5-yl) -7-but-3-ynyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2, 6-dione; (4S, 7R, 8S, 9S, 13Z, 16S) -16- (2-aminomethyl-benzoxazol-5-yl) -4,8-dihydroxy-7-but-3-ynyl-5,5, 9,13-tetramethyl-oxacyclohexadec-13-en-2,6-dione; (1S, 3S, 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10-but-3-ynyl-8, 8,12,16-tetramethyl-3- (2-methyl-benzoxazol-5-yl) -4,17-dioxabicyclo [14.1.0] heptadecan-5,9-dione; (1S, 3S, 7S, 10R, 11 , 12S, 16R) -7,11-dihydroxy-3- (2-hydroxymethylbenzoxazol-5-yl) -10-but-3-ynyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo [ 14.1.0] heptadecan-5,9-dione; (1S, 3S, 7S, 10R, 11 S, 12S, 16R) -3- (2-aminomethyl-benzoxazol-5-yl) -7,11-dihydroxy-10 -but-3-ynyl-8,8,12,16-tetramethyl-4,17- dioxa-bicyclo [14.1.0] heptadecane-5,9-dione, where the hydrogen atoms in the abovementioned effector bases are replaced by radicals L ¹ -L ³ at the positions indicated in formula (1). Effector conjugate according to one of claims 1-3, with the linker selected is from the group consisting of compounds of the general formula (III), where V represents a bond or an aryl radical, O Is zero, and T is an oxygen atom. Effector-recognition unit conjugate of the general formula (1),

wherein the substituents therein have the meanings given in claim 1, but at least one group FG ^{1 has been} replaced by a group FG ² , where FG ^{2 can have} the following meanings:

wherein a recognition unit is conjugated to the group FG ² via a sulfur atom; wherein the recognition unit is selected from the group consisting of peptides, soluble receptors, cytokines, lymphokines, aptamers, Spiegelmeres, recombinant proteins, new framework structures, monoclonal antibodies, and fragments of monoclonal antibodies; as a uniform isomer or a mixture of different isomers and / or as a pharmaceutically acceptable salt thereof. The effector recognition unit conjugate according to claim 5, wherein the conjugate contains more than one recognition unit, and wherein the recognition units are identical. The effector-recognition unit conjugate according to claim 5 or 6, wherein the recognition unit is an antibody, or an antigen-binding fragment thereof, which is specific for an antigen selected from the group consisting of the antigens listed in Table 1, and CD19 , CD20, CD40, CD22, CD25, CDS, CD52, CD10, CD2, CD7, CD33, CD38, CD40, CD72, CD4, CD21, CD37, CD30, VCAM, CD31, ELAM, Endoglin, VEGFRI / II, α _v β ₃ , Tie1 / 2, TES23 (CD44ex6), phosphatidylserine, PSMA, VEGFR / VEGF complex and ED-B fibronectin. Linker of the general formula (III ¹ :

wherein RG ^{1 is} an O = C = N group or an S = C = N group, and o, V, q and FG ^{1 have} the meanings given in claim 1; or linker of the general formula (III ² ):

wherein RG ^{2 is} a Hal-C (= T) -CHR ²² group or a Hal-C (= T) -CHR ²² -NR ²³ -C (= T) group or one R ²⁶ -C (= O) -OC (= T) -CHR ²² group or an R ²⁶ -C (= O) -OC (= T) -CHR ²² -NR ²³ -C (= T) group , wherein R ^{26 is} C ₁ -C ₁₀ alkyl, aryl, aralkyl, and o, V, q and FG ^{1 have} the meanings given in claim 1; or linker of the general formula (III ³ ):

wherein RG ^{3 is} an OH group or an NHR ^24a group or a COOH group, and o, V, q and FG ^{1 have} the meanings given in claim 1; however, provided that the compound 1- (4-aminophenyl) pyrrole-2,5-dione is not included. Linker according to claim 8, where V represents a bond or an aryl radical, o is the same Is zero and T is an oxygen atom. A process for the preparation of effector conjugates according to any one of claims 1-4, wherein a compound of general formula (I), wherein the substituents have the meanings given in claim 1, but the condition that at least one substituent L ¹ , L ² or L ^{4 represents} a linker of the general formula (III), need not be satisfied, and represents at least one substituent L ¹ , L ² or L ⁴ hydrogen, a group C (= O) Cl, or a group C (= S) Cl ; with a linker selected from the group consisting of a linker of the general formula (III ¹ ) or (III ² ) or (III ³ ) as described in claim 8. Process for the preparation of effector recognition unit conjugates according to one of claims 5 to 7, wherein an effector conjugate according to any one of claims 1-4 with at least a recognition unit, as defined in claims 5 and 7, implemented becomes. Use of a compound of the general formula (I), where the substituents have the meanings given in claim 1, but the condition that at least one substituent L ¹ , L ² or L ^{4 is} a linker of the general formula (III) is not met must, and at least one substituent L ¹ , L ² or L ^{4 represents} hydrogen, a group C (= O) Cl, or a group C (= S) Cl; in a method according to claim 10. Use of a compound of general formula (I) for the preparation an effector-recognition unit conjugate according to claims 5 to 7. Use of a linker of the general formula (III ¹ ), (III ² ) or (III ³ ) in a process according to claim 10. Use of a linker of the general formula (III ¹ ), (III ² ) or (III ³ ) for the production of an effector-recognition unit conjugate according to one of Claims 5 to 7. Use of a recognition unit as in claim 5 or 7 defined in a method according to claim 11. Effector-recognition unit conjugate according to one of claims 5 to 7 for use as a medicament. Effector-recognition unit conjugate according to one of claims 5 to 7 for use as a medicament for the treatment of diseases, associated with proliferative processes. Effector-recognition unit conjugate according to one of claims 5 to 7 for use as a medicament to treat a disease, the selected is from the group consisting of tumors, inflammatory diseases, neurodegenerative Diseases, angiogenesis-associated diseases, multiple sclerosis, Alzheimer's and rheumatoid arthritis.