Effector conjugates, process for their production and their pharmaceutical use Number:7,129,254 from the United States Patent and Trademark Office (PTO) owispatent Conjugates of epothilones and epothilone derivatives (as effectors) with suitable biomolecules (as recognition units) are described. Their production is carried out by the effectors being reacted with suitable linkers, and the compounds that are produced are conjugated to the recognition units. The pharmaceutical use of the conjugates for treating proliferative or angiogenesis-associated processes is described.<H pharmaceutical, production, Effector, conjug, 7129254.html, Patent, pto, 7129254

Title: Effector conjugates, process for their production and their pharmaceutical use

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

Patent Number: 7,129,254 Issued on 10/31/2006 to Berger, et al.

Inventors: Berger; Markus (Berlin, DE), Siemeister; Gerhard (Berlin, DE), Klar; Ulrich (Berlin, DE), Willuda; Jorg (Berlin, DE), Menrad; Andreas (Oranienburg, DE), Bosslet; Klaus (Berlin, DE)
Assignee: Schering Aktiengesellschaft (Berlin, DE)

Appl. No.: 10/631,011

Filed: July 31, 2003

Foreign Application Priority Data


Jul 31, 2002 [DE]			102 34 975
Feb 07, 2003 [DE]			103 05 098

Current U.S. Class: 514/340 ; 514/365; 514/372; 514/374; 546/268.1; 548/146; 548/206; 548/215; 549/357

Current International Class: A61K 31/425 (20060101); A61K 31/44 (20060101); C07D 277/20 (20060101); C07D 417/08 (20060101)

Field of Search: 514/340,365,374,378,372 546/268.1 548/146,206,215,240 549/357

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Primary Examiner: Solola; Taofiq
Attorney, Agent or Firm: Millen, White, Zelano & Branigan, P.C.

Claims

The invention claimed is:

1. An effector recognition unit conjugate of formula (I), ##STR00025## wherein R.sup.1a and R.sup.1b are, independently of one another, hydrogen, C.sub.1 C.sub.10 alkyl, aryl, aralkyl, or together a --(CH.sub.2).sub.m group, in which m is 2 to 5, one of R.sup.2a and R.sup.2b is ##STR00026## and the other one of R.sup.2a and R.sup.2b is hydrogen, C.sub.1 C.sub.10 alkyl, aryl, aralkyl, or C.sub.2 C.sub.10 alkenyl, or C.sub.2 C.sub.10 alkynyl, R.sup.3 is hydrogen, C.sub.1 C.sub.10 alkyl, aryl or aralkyl, and R.sup.4a and R.sup.4b are, independently of one another, hydrogen, C.sub.1 C.sub.10 alkyl, aryl, aralkyl, or together a --(CH.sub.2).sub.p group, in which p is 2 to 5, R.sup.5 is hydrogen, C.sub.1 C.sub.10 alkyl, aryl, aralkyl, CO.sub.2H, CO.sub.2alkyl, CH.sub.2OH, CH.sub.2Oalkyl, CH.sub.2Oacyl, CN, CH.sub.2NH.sub.2, CH.sub.2N(alkyl, acyl).sub.1,2, or CH.sub.2Hal, Hal is a halogen atom, R.sup.6 and R.sup.7 are, in each case are hydrogen, or together an additional bond, or together an oxygen atom, or together an NH group, or together an N-alkyl group, or together a CR.sub.2 group, G is an oxygen atom or CH.sub.2, D-E is a group H.sub.2C--CH.sub.2, HC.dbd.CH, C.ident.C, CH(OH)--CH(OH), CH(OH)--CH.sub.2, CH.sub.2--CH(OH), ##STR00027## W is a group C(.dbd.X)R.sup.8, or a bicyclic or tricyclic aromatic or heteroaromatic radical, L.sup.3 is hydrogen, or, if a radical in W contains a hydroxyl group, forms a group O-L.sup.4 with the latter, or, if a radical in W contains an amino group, forms a group NR.sup.25-L.sup.4 with the latter, R.sup.25 is hydrogen or C.sub.1 C.sub.10 alkyl, X is an oxygen atom, R.sup.8 is hydrogen, C.sub.1 C.sub.10 alkyl, aryl, aralkyl, halogen or CN, and Z is oxygen or is an H and OR.sup.12 group, R.sup.12 is hydrogen or a protective group PG.sup.Z, A-Y is O--C(.dbd.O), O--CH.sub.2, CH.sub.2--C(.dbd.O), or NR.sup.21--C(.dbd.O), R.sup.21 is a hydrogen atom or C.sub.1 C.sub.10 alkyl, PG.sup.X, PG.sup.Y, and PG.sup.Z are a protective group PG, and L.sup.1, L.sup.2, and L.sup.4 are, independently of one another, hydrogen, a group C(.dbd.O)Cl, a group C(.dbd.S)Cl, a group PG.sup.Y or a linker of formula (III) or (IV); provided that at least one substituent L.sup.1, L.sup.2 or L.sup.4 represents a linker of formula (III) or (IV); the linker of formula (III) has the following structure, ##STR00028## in which T is oxygen or sulfur, U is oxygen, CHR.sup.22, CHR.sup.22--NR.sup.23--C(.dbd.O)--, O--C(.dbd.O)--CHR.sup.22--NR.sup.23--C(.dbd.O)--, O--C(.dbd.O)--CHR.sup.22--NR.sup.23--C(.dbd.S)--, CHR.sup.22--NR.sup.23--C(.dbd.S)-- or NR.sup.24a, o is 0 to 15, V is a bond, aryl, a group ##STR00029## s is 0 to 4, Q is a bond, O--C(.dbd.O)--NR.sup.24c, O--C(.dbd.S)--NR.sup.24c, ##STR00030## R.sup.22 is hydrogen, C.sub.1 C.sub.10 alkyl, aryl or aralkyl, R.sup.23 is hydrogen or C.sub.1 C.sub.10 alkyl, R.sup.24a, R.sup.24b, and R.sup.24c are, independently of one another, hydrogen or C.sub.1 C.sub.10 alkyl, q is 0 to 15, FG.sup.1 is C.sub.1 C.sub.10 alkyl-S.sub.3, ##STR00031## or CO.sub.2H; and the linker of formula (IV) has the following structure, ##STR00032## in which T is oxygen or sulfur, W.sup.1 and W.sup.2 are the same or different and are oxygen or NR.sup.24a, o is 0 to 5, R.sup.24a is hydrogen or C.sub.1 C.sub.10 alkyl, R.sup.27 is halogen, CN, NO.sub.2, CO.sub.2R.sup.28, or OR.sup.28, R.sup.28 is hydrogen, C.sub.1 C.sub.10 alkyl, aryl or aralkyl, q is 0 to 5, U is oxygen, CHR.sup.22, CHR.sup.22--NR.sup.23--C(.dbd.O)--, CHR.sup.22--NR.sup.23--C(.dbd.S)-- or C.sub.1 C.sub.20 alkyl, R.sup.22 is hydrogen, C.sub.1 C.sub.10 alkyl, aryl or aralkyl, R.sup.23 is hydrogen or C.sub.1 C.sub.10 alkyl, r is 0 to 20, FG.sup.1 is C.sub.1 C.sub.10 alkyl-S.sub.3, ##STR00033## or CO.sub.2H, and wherein at least one group FG.sup.1 is not as defined above, but instead is a group FG.sup.2a or FG.sup.2b, wherein FG.sup.2a is --S--S--, ##STR00034## and FG.sup.2b is --CONH--; wherein a recognition unit is conjugated via a sulfur atom with group FG.sup.2a or via an amide function with group FG.sup.2b; and wherein the recognition unit is selected from peptides, soluble receptors, cytokines, lymphokines, aptamers, spiegelmers, recombinant proteins, new framework structures, monoclonal antibodies and fragments of monoclonal antibodies; or a single isomer or a mixture of different isomers or a pharmaceutically acceptable salt thereof.

2. An effector recognition unit conjugate according to claim 1, wherein the effector element is (4S,7R,8S,9S,13Z,16S)-4,8-Dihydroxy-7-allyl-5,5,9,13-tetramethyl-16-(2met- hyl-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-d- ione; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-benzoth- iazol-5-yl)-10-allyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]hepta- decane-5,9-dione; (1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzothiazol-5-yl)-7,11-dihyd- roxy-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-allyl-5,5,9,13-tetramethy- l-16-(2methyl-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-dio- ne; (1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-(2-hydroxymethyl-benzoxazo- l-5-yl)-10-allyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadeca- ne-5,9-dione; (1S,3S,7S,10R,11S,12S,16R)-3-(2-Aminomethyl-benzoxazol-5-yl)-7,11-dihydro- xy-10-allyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,- 9-dione; wherein the hydrogen atoms in the above-mentioned effector elements are replaced in the positions indicated in formula (I) by radicals L.sup.1 L.sup.3.

3. An effector recognition unit conjugate according to claim 1, wherein the linker is a compound of formula (III), wherein V represents a bond or an aryl radical, o is zero, and T is an oxygen atom.

4. An effector recognition unit conjugate according to claim 1, wherein the linker is a compound of formula (III), wherein V represents a bond or an aryl radical or a group ##STR00035## o is 0 to 4, and Q is a bond or a group ##STR00036##

5. An effector recognition unit conjugate according to claim 4, wherein V is a bond or a group ##STR00037## Q is a bond or a group ##STR00038## o is 0, 2 or 3, s is 1, and T is an oxygen atom.

6. An effector recognition unit conjugate according to claim 1, wherein the linker is a compound of formula (IV), wherein o is 0 to 4, and q is 0 to 3.

7. An effector recognition unit conjugate according to claim 6, wherein o is 0, 2 or 3, W.sup.1 is oxygen, q is 0, R.sup.22 is hydrogen, C.sub.1 C.sub.3 alkyl or aralkyl, R.sup.23 is hydrogen or C.sub.1 C.sub.3 alkyl, R.sup.24a is hydrogen or C.sub.1 C.sub.3 alkyl, R.sup.27 is fluorine, chlorine, CN, NO.sub.2, CO.sub.2R.sup.28 or OR.sup.28, R.sup.28 is hydrogen or C.sub.1 C.sub.5 alkyl, and U is oxygen, CHR.sup.22, or CHR.sup.22--NR.sup.23--C(.dbd.O)--.

8. An effector recognition unit conjugate according to claim 1, wherein the conjugate contains more than one recognition unit, and wherein the recognition units are identical.

9. An effector recognition unit conjugate according to claim 1, wherein the recognition unit is an antibody, or an antigen-binding fragment thereof, which is specific for an antigen that is selected from OC 125, OC 133, OMI, Mo v1, Mo v2, 3C2, 4C7, ID3, DU-PAN-2, F 36/22, 4F7/7A 10, OV-TL3, B72.3, DF3, 2C8/2F7, MF 116, Mov18, CEA 11-H5, CA 19-9, (1116NS 19-9), H17-E2, 791T/36, NDOG2, H317, 4D5, 3H4, 7C2, 6E9, 2C4, 7F3, 2H11, 3E8, 5B8, 7D3, SB8, HMFG2, 3.14.A3, DF3, NCRC-11, 3C6F9, MBE6, CLNH5, MAC 40/43, EMA, HMFG1 HFMG2, 3.15.C3, M3, M8, M24, M18, 67-D-11, D547Sp, D75P3, H222, Anti EGF, LR-3, TA1, H59, 10-3D-2, HmAB1,2, MBR 1,2,3, 24-17-1, 24-17-2 (3E1-2), F36/22, M7/105, C11, G3, H7, B6-2, B1-1, Cam 17-1, SM3, SM4, C-Mul (566), 4D5 3H4, 7C2, 6E9, 2C4, 7F3, 2H11, 3E8, 5B8, 7D3, 5B8, OC 125, MO v2, DU-PAN-2, 4F7/7A10, DF3, B72-3, cccccCEA 11, H17-E2, 3-14-A3, FO23C5, B72-3, (17-1A) 1038-17-1A, CO17-1A, ZCE-025, AB2, HT-29-15, 250-30.6, 44X14, A7, GA73-3, 791T/36, 28A32, 28.19.8, X MMCO-791, DU-PAN-2, ID3, CEA, 11-H5, 2C8/2F7, CA-19-9 (1116NS 19-9), PR5C5, PR4D2, PR4D1, 4-1, 8-2 M17, 96-5, 118-1, 133-2, (113-2), L1, L10, R10 (R19), I12, K5, 6-1, R24, 5-1, 225.28S, 465.12S, 9-2-27, F11, 376.96S, 465.12S, 15-75, 15-95, Mel-14, Mel-12, Me3-TB7, 225.28SD, 763.24TS, 705F6, 436910, M148, ID3, DU-PAN-2, OV-TL3, B72-3, CEA 11-H5, 3-14-A3,C COLI, CA-19-9, 1116NS 19-9) and CA50, OC125, 4D5, 3H4, 7C2, 6E9, 2C4, 7F3, 2H11, 3E8, 5B8, 7D3, SB8, MC v2, B72-3, DU-PAN-2, CEA 11-H5, MUG 8-22, MUG 2-63, MUC 2-39, MUG 7-39, PAb 240, PAb 246, PAb 1801, ERIC-1, M148, FMH25, 6-1, CA1, 3F8, 4F7/7A10, 2C8/2F7, CEA, 11-H5, 2H8, 10G6, CD19, CD20, CD40, CD22, CD25, CD5, CD52, CD10, CD2, CD7, CD33, CD38, CD40, CD72, CD4, CD21, CD37, CD30, VCAM, CD31, ELAM, endoglin, VEGFRI/II, .alpha..sub.v.beta..sub.3, Tie1/2, TES23 (CD44ex6), phosphatidylserine, PSMA, VEGFR/VEGF complex and ED-B-fibronectin.

10. An effector recognition unit conjugate according to claim 1, wherein Z is oxygen.

11. A method for preparing an effector recognition unit conjugate according to claim 1 comprising reacting an effector conjugate of formula (I) with at least one recognition unit selected from peptides, soluble receptors, cytokines, lymphokines, aptamers, spiegelmers, recombinant proteins, new framework structures, monoclonal antibodies and fragments of monoclonal antibodies.

12. A method according to claim 11, wherein the effector conjugate of formula (I), is prepared by reacting a compound of formula (I), wherein at least one substituent L.sup.1, L.sup.2 or L.sup.4 represent a linker of formula (III) or (IV), and at least one substituent L.sup.1, L.sup.2 or L.sup.4 represents hydrogen, a group C(.dbd.O)Cl, or a group C(.dbd.S)Cl, with a linker that is selected from a linker of formula (III.sup.1), (III.sup.2), (III.sup.3), (IV.sup.1), (IV.sup.2) and (IV.sup.3), ##STR00039## in which RG.sup.1 is an O.dbd.C.dbd.N group or an S.dbd.C.dbd.N group, o is 0to 15, V is a bond, aryl, a group ##STR00040## q is 0 to 15, FG.sup.1 is C.sub.1 C.sub.10 alkyl-S.sub.3, ##STR00041## or CO.sub.2H; ##STR00042## in which RG.sup.2 is a Hal-C(=T)-CHR.sup.22 group, or a Hal-C(=T)-CHR.sup.22--NR.sup.23--C(=T) group, or an R.sup.26--C(.dbd.O)--O--C(=T)-CHR.sup.22 group, or an R.sup.26--C(.dbd.O)--O--C(=T)-CHR.sup.22--NR.sup.23--C(=T) group, wherein R.sup.26 is C.sub.1 C.sub.10 alkyl, aryl, or aralkyl, o is 0 to 15, V is a bond, aryl, a group ##STR00043## q is 0 to 15, FG.sup.1 is C.sub.1 C.sub.10 alkyl-S.sub.3, ##STR00044## or CO.sub.2H; ##STR00045## in which RG.sup.3 is an OH group, or an NHR.sup.24a group, or a COOH group, o is 0 to 15, V is a bond, aryl, a group ##STR00046## q is 0 to 15, FG.sup.1 is C.sub.1 C.sub.10 alkyl-S.sub.3, ##STR00047## or CO.sub.2H; with the proviso that the compound 1-(4-amino-phenyl)-pyrrole-2,5-dione is not included; ##STR00048## in which RG.sup.1 is an O.dbd.C.dbd.N group or an S.dbd.C.dbd.N group, W.sup.2 is oxygen or NR.sup.24a, o is 0 to 5, R.sup.27 is halogen, CN, NO.sub.2, CO.sub.2R.sup.28, or OR.sup.28, q is 0 to 5, U is oxygen, CHR.sup.22, CHR.sup.22--NR.sup.23--C(.dbd.O)--, CHR.sup.22--NR.sup.23--C(.dbd.S)-- or C.sub.1 C.sub.20 alkyl, r is 0to 20, FG.sup.1 is C.sub.1 C.sub.10 alkyl-S.sub.3, ##STR00049## or CO.sub.2H, ##STR00050## in which RG.sup.2 is a Hal-C(=T)-CHR.sup.22 group, or a Hal-C(=T)-CHR.sup.22--NR.sup.23--C(=T) group, or an R.sup.26--C(.dbd.O)--O--C(=T)-CHR.sup.22 group, or an R.sup.26--C(=O)--O--C(=T)-CHR.sup.22--NR.sup.23--C(=T) group, wherein R.sup.26 is C.sub.1 C.sub.10 alkyl, aryl, or aralkyl, T is oxygen or sulfur, W.sup.2 is oxygen or NR.sup.24a, o is 0 to 5, R.sup.27 is halogen, CN, NO.sub.2, CO.sub.2R.sup.28, or OR.sup.28, q is 0 to 5, U is oxygen, CHR.sup.22, CHR.sup.22--NR.sup.23--C(.dbd.O)--, CHR.sup.22--NR.sup.23--C(.dbd.S)-- or C.sub.1 C.sub.20 alkyl, R.sup.22 is hydrogen, C.sub.1 C.sub.10 alkyl, aryl or aralkyl, R.sup.23 is hydrogen or C.sub.1 C.sub.10 alkyl, r is 0 to 20, FG.sup.1 is C.sub.1 C.sub.10 alkyl-S.sub.3, ##STR00051## or CO.sub.2H, ##STR00052## in which RG.sup.3 is an OH group or an NHR.sup.24a group or a COOH group, W.sup.2 is oxygen or NR.sup.24a, o is 0 to 5, R.sup.24a is hydrogen or C.sub.1 C.sub.10 alkyl, R.sup.27 is halogen, CN, NO.sub.2, CO.sub.2R.sup.28, or OR.sup.28, q is 0 to 5, U is oxygen, CHR.sup.22, CHR.sup.22--NR.sup.23--C(.dbd.O)--, CHR.sup.22--NR.sup.23--C(.dbd.S)-- or C.sub.1 C.sub.20 alkyl, r is 0 to 20, FG.sup.1 is C.sub.1 C.sub.10 alkyl-S.sub.3, ##STR00053## or CO.sub.2H.

13. A method according to claim 11, wherein in the effector conjugate of formula (I) at least one substituent L.sup.1, L.sup.2 or L.sup.4 represent a linker of formula (III) or (IV), and at least one substituent L.sup.1, L.sup.2 or L.sup.4 represents hydrogen, a group C(.dbd.O)Cl, or a group C(.dbd.S)Cl.

14. A pharmaceutical composition comprising an effector recognition unit conjugate according to claim 1 and a pharmaceutically acceptable carrier.

15. A method for treating a tumor comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition according to claim 14.

Description

The development of the understanding relating to the recognition of binding regions, especially in the field of monoclonal antibodies or fragments thereof against specific tumor antigens, makes it possible to consider a selective tumor therapy by specific release of an anti-tumor active agent at the target site.

A precondition for such an approach, in which a highly active (toxic) active agent (effector) is coupled to a high-molecular, tumor-specific recognition unit, such as, for example, to an antibody, is a substantial inactivity of the conjugate, whose minimum components are represented by a recognition unit and an effector, until it has reached the target site (tumor). Arriving at the target site, the conjugate binds to the cell surface and the active ingredient, optionally after the preceding internalization of the entire complex, can be released.

The successful therapy of solid tumors, especially with monoclonal antibodies, can be limited, however, by an inadequate penetration of the antibody into the tumor as well as the heterogeneous dispersion of the corresponding tumor-associated antigens in the tumor tissue.

These limitations could be avoided in that the tumor-vascular system is attacked in a specific way. The growth of tumors below a volume of about 2 mm.sup.3 depends on a neoangiogenesis. The subsequent tumor growth is based on an intact vascular system, which ensures the supply with nutrients or the removal of waste products. The selective destruction of this system should therefore result in a necrosis of the tumor. The attack on the vascular system of the tumor promises a number of advantages relative to the direct attack on the tumor itself. In comparison to tumor cells, endothelial cells are easier to access, since no tumor tissue has to be penetrated. The damage of an individual tumor vessel should result in a necrosis of thousands of tumor cells. To damage a tumor vessel, it is not necessary to kill all endothelial cells. The specific attack of endothelial cells in or close to the tumors minimizes systemic side effects. Endothelial cells are genetically very stable, so that the probability of a development of resistance against the tumor therapeutic agent is low.

Within the scope of this invention, surprisingly enough, a possibility has now been found to link the chemically very sensitive, highly-functionalized class of active agents of epothilones and analogs thereof to a high-molecular recognition unit via different linkers in different positions of the active agent.

The object of this invention is thus, inter alia, 1. to find a method to link highly active active agents from the structural class of the epothilones and epothilone derivatives with suitable linkers, 2. to synthesize suitable linkers, 3. to develop a method to link these epothilone-linker conjugates to recognition units, such as, for example, monoclonal antibodies or fragments thereof, to form immune conjugates that are both chemically and metabolically sufficiently stable for the development of a pharmaceutical, and that are superior to the epothilones or epothilone derivatives that are taken as a basis with respect to their therapeutic range, their selectivity of action and/or undesirable toxic side effects and/or the degree of their activity. This invention accordingly comprises effector conjugates of general formula I

##STR00001## in which R.sup.1a, R.sup.1b, independently of one another, are hydrogen, C.sub.1 C.sub.10 alkyl, aryl, aralkyl, or together a --(CH.sub.2).sub.m group, in which m is 2 to 5, R.sup.2a, R.sup.2b, independently of one another, are hydrogen, C.sub.1 C.sub.10 alkyl, aryl, aralkyl, or together a --(CH.sub.2).sub.n group, in which n is 2 to 5, or C.sub.2 C.sub.10 alkenyl, or C.sub.2 C.sub.10 alkynyl, R.sup.3 is hydrogen, C.sub.1 C.sub.10 alkyl, aryl or aralkyl, and R.sup.4a, R.sup.4b, independently of one another, are hydrogen, C.sub.1 C.sub.10 alkyl, aryl, aralkyl, or together a --(CH.sub.2).sub.p group, in which p is 2 to 5, R.sup.5 is hydrogen, C.sub.1 C.sub.10 alkyl, aryl, aralkyl, CO.sub.2H, CO.sub.2alkyl, CH.sub.2OH, CH.sub.2OAlkyl, CH.sub.2OAcyl, CN, CH.sub.2NH.sub.2, CH.sub.2N(alkyl, acyl).sub.12, or CH.sub.2Hal, Hal is a halogen atom, R.sup.6, R.sup.7 in each case are hydrogen, or together an additional bond, or together an oxygen atom, or together an NH group, or together an N-alkyl group, or together a CH.sub.2 group, and G is an oxygen atom or CH.sub.2, D-E is a group H.sub.2C--CH.sub.2, HC.dbd.CH, C.ident.C, CH(OH)--CH(OH), CH(OH)--CH.sub.2, CH.sub.2--CH(OH),

##STR00002## O--CH.sub.2, or, if G represents a CH.sub.2 group, D-E is CH.sub.2--O, W is a group C(.dbd.X)R.sup.8, or a bi- or tricyclic aromatic or heteroaromatic radical, L.sup.3 is hydrogen, or, if a radical in W contains a hydroxyl group, forms a group O-L.sup.4 with the latter, or, if a radical in W contains an amino group, forms a group NR.sup.25-L.sup.4 with the latter, R.sup.25 is hydrogen or C.sub.1 C.sub.10 alkyl, X is an oxygen atom, or two OR.sup.20 groups, or a C.sub.2 C.sub.10 alkylenedioxy group that may be straight-chain or branched, or H/OR.sup.9, or a CR.sup.10R.sup.11 group, R.sup.8 is hydrogen, C.sub.1 C.sub.10 alkyl, aryl, aralkyl, halogen or CN, and R.sup.9 is hydrogen or a protective group PG.sup.X, R.sup.10, R.sup.11 in each case independently of one another, are hydrogen, C.sub.1 C.sub.20 alkyl, aryl, aralkyl, or together with a methylene carbon atom form a 5- to 7-membered carbocyclic ring, Z can represent oxygen or H/OR.sup.12, R.sup.12 can represent hydrogen or a protective group PG.sup.Z, A-Y can represent a group O--C(.dbd.O), O--CH.sub.2, CH.sub.2--C(.dbd.O), NR.sup.21--C(.dbd.O) or NR.sup.21--SO.sub.2, R.sup.20 can represent C.sub.1 C.sub.20 alkyl, R.sup.21 can represent a hydrogen atom or C.sub.1 C.sub.10 alkyl, PG.sup.X, PG.sup.Y, and PG.sup.Z can represent a protective group PG, and L.sup.1, L.sup.2, and L.sup.4, independently of one another, can represent hydrogen, a group C(.dbd.O)Cl, a group C(.dbd.S)Cl, a group PG.sup.Y or a linker of general formula (III) or (IV); provided that at least one substituent L.sup.1, L.sup.2 or L.sup.4 represents a linker of general formula (III) or (IV); the linker of general formula (III) has the following structure,

##STR00003## in which T can represent oxygen or sulfur, U can represent oxygen, CHR.sup.22, CHR.sup.22--NR.sup.23--C(.dbd.O)--, CHR.sup.22--NR.sup.23--C(.dbd.S)--, O--C(.dbd.O)--CHR.sup.22--NR.sup.23--C(.dbd.O)--, O--C(.dbd.O)--CHR.sup.22--NR.sup.23--C(.dbd.S)-- or NR.sup.24a, o can represent 0 to 15, V can represent a bond, aryl, a group

##STR00004## or a group

##STR00005## s can represent 0 to 4, Q can represent a bond, O--C(.dbd.O)--NR.sup.24c, O--C(.dbd.S)--NR.sup.24c,

##STR00006## R.sup.22 can represent hydrogen, C.sub.1 C.sub.10 alkyl, aryl or aralkyl, R.sup.23 can represent hydrogen or C.sub.1 C.sub.10 alkyl, R.sup.24a, R.sup.24b, and R.sup.24c, independently of one another, can represent hydrogen or C.sub.1 C.sub.10 alkyl, q can represent 0 to 15, FG.sup.1 can represent C.sub.1 C.sub.10 alkyl-S.sub.3,

##STR00007## or CO.sub.2H; and the linker of general formula (IV) has the following structure,

##STR00008## in which T can represent oxygen or sulfur, W.sup.1, W.sup.2 are the same or different and can represent oxygen or NR.sup.24a, o can represent 0 to 5, R.sup.22 can represent hydrogen, C.sub.1 C.sub.10 alkyl, aryl or aralkyl, R.sup.23 can represent hydrogen, or C.sub.1 C.sub.10 alkyl, R.sup.24a can represent hydrogen or C.sub.1 C.sub.10 alkyl, R.sup.27 can represent halogen, CN, NO.sub.2, CO.sub.2R.sup.28, or OR.sup.28, R.sup.28 can represent hydrogen, C.sub.1 C.sub.10 alkyl, aryl or aralkyl, q can represent 0 to 5, U can represent oxygen, CHR.sup.22, CHR.sup.22--NR.sup.23--C(.dbd.O)--, CHR.sup.22--NR.sup.23--C(.dbd.S)-- or C.sub.1 C.sub.20 alkyl, r can represent 0 to 20, FG.sup.1 can represent C.sub.1 C.sub.10 alkyl-S.sub.3,

##STR00009## or CO.sub.2H, as a single isomer or a mixture of different isomers and/or as a pharmaceutically acceptable salt thereof.

In addition, the invention describes the production of effector recognition unit conjugates of general formula (I), wherein the substituents therein have the above-mentioned meanings, but at least one group FG.sup.1 is replaced by a group FG.sup.2a or FG.sup.2b, wherein FG.sup.2a or FG.sup.2b can have the following meanings:

FG.sup.2a: --S--S--,

##STR00010##

FG.sup.2b: --CONH--

and wherein a recognition unit is conjugated via a sulfur atom with the group FG.sup.2a, wherein the indicated sulfur atom is a component of the recognition unit, or via an amide function of group FG.sup.2b, wherein the indicated nitrogen atom is a component of the recognition unit; wherein the recognition unit can be, for example, a peptide, a soluble receptor, a cytokine, a lymphokine, an aptamer, a spiegelmer, a recombinant protein, a framework structure, a monoclonal antibody or a fragment of a monoclonal antibody.

According to this invention, the above-mentioned effector recognition unit conjugates can comprise one or more recognition units; in this case, the recognition units that belong to a conjugate can be identical or different. It is preferred that the recognition units of a conjugate be identical.

The effector recognition unit conjugates according to the invention can be used in the form of their .alpha.-, .beta.- or .gamma.-cyclodextrin-clathrates or in the form of liposomal or pegylated compositions.

The conjugates according to the invention are preferably used for the treatment of diseases that are associated with proliferative processes. For example, the therapy of different tumors, the therapy of inflammatory and/or neurodegenerative diseases, such as multiple sclerosis or Alzheimer's disease, the therapy of angiogenesis-associated diseases such as the growth of solid tumors, rheumatoid arthritis or diseases of the ocular fundus, can be mentioned.

The production of epothilones, their precursors and derivatives of general formula I is carried out according to the methods that are known to one skilled in the art, as they are described in, for example, DE 19907588, WO 98/25929, WO 99/58534, WO 99/2514, WO 99/67252, WO 99/67253, WO 99/7692, EP 99/4915, WO 00/485, WO 00/1333, WO 00/66589, WO 00/49019, WO 00/49020, WO 00/49021, WO 00/71521, WO 00/37473, WO 00/57874, WO 01/92255, WO 01/81342, WO 01/73103, WO 01/64650, WO 01/70716, U.S. Pat. No. 6,204,388, U.S. Pat. No. 6,387,927, U.S. Pat. No. 6,380,394, U.S. Ser. No. 02/52028, U.S. Ser. No. 02/58286, U.S. Ser. No. 02/62030, WO 02/32844, WO 02/30356, WO 02/32844, WO 02/14323, and WO 02/8440.

As alkyl groups R.sup.1a, R.sup.1b, R.sup.2a, R.sup.2b, R.sup.3, R.sup.4a, R.sup.4b, R.sup.5, R.sup.8, R.sup.10, R.sup.11, R.sup.20, R.sup.21, R.sup.22, R.sup.23, R.sup.24a, R.sup.24b, R.sup.24c, R.sup.25 and R.sup.26, straight-chain or branched-chain alkyl groups with 1 20 carbon atoms can be considered, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, and decyl.

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

As aryl radicals R.sup.1a, R.sup.1b, R.sup.2a, R.sup.2b, R.sup.3, R.sup.4a, R.sup.4b, R.sup.5, R.sup.8, R.sup.10, R.sup.11, R.sup.22, R.sup.26 and V, substituted and unsubstituted carbocyclic or heterocyclic radicals with one or more heteroatoms, such as phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl, benzothiazolyl or benzoxazolyl, which can be substituted in one or more places by halogen, OH, O-alkyl, CO.sub.2H, CO.sub.2-alkyl, --NH.sub.2, --NO.sub.2, --N.sub.3, --CN, C.sub.1 C.sub.20-alkyl, C.sub.1 C.sub.20-acyl or C.sub.1 C.sub.20-acyloxy groups, are suitable. The heteroatoms can be oxidized provided that this does not cause the aromatic character to be lost, such as, for example, the oxidation of a pyridyl to a pyridyl-N-oxide.

As bicyclic and tricyclic aryl radicals W, substituted and unsubstituted, carbocyclic or heterocyclic radicals with one or more heteroatoms such as naphthyl, anthryl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolyl, isoquinolyl, benzoxazinyl, benzofuranyl, indolyl, indazolyl, quinoxalinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thienopyridinyl, pyridopyridinyl, benzopyrazolyl, benzotriazolyl, or dihydroindolyl, which can be substituted in one or more places by halogen, OH, O-alkyl, CO.sub.2H, CO.sub.2-alkyl, --NH.sub.2, --NO.sub.2, --N.sub.3, --CN, C.sub.1 C.sub.20-alkyl, C.sub.1 C.sub.20-acyl or C.sub.1 C.sub.20-acyloxy groups, are suitable. The heteroatoms can be oxidized provided that this does not cause the aromatic character to be lost, such as, for example, the oxidation of a quinolyl to a quinolyl-N-oxide.

The aralkyl groups in R.sup.1a, R.sup.1b, R.sup.2a, R.sup.2b, R.sup.3, R.sup.4a, R.sup.4b, R.sup.5, R.sup.8, R.sup.10, R.sup.11, R.sup.22 and R.sup.26 can contain in the ring up to 14 C atoms, preferably 6 to 10 C atoms, and in the alkyl chain 1 to 8 atoms, preferably 1 to 4 atoms. As an aralkyl radical, for example, benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl or pyridylpropyl is suitable. The rings can be substituted in one or more places by halogen, OH, O-alkyl, CO.sub.2H, CO.sub.2-alkyl, --NO.sub.2, --N.sub.3, --CN, C.sub.1 C.sub.20-alkyl, C.sub.1 C.sub.20-acyl or C.sub.1 C.sub.20-acyloxy groups.

As representatives of protective groups PG, tris(C.sub.1 C.sub.20 alkyl)silyl, bis(C.sub.1 C.sub.20 alkyl)-arylsilyl, (C.sub.1 C.sub.20 alkyl)-diarylsilyl, tris(aralkyl)-silyl, C.sub.1 C.sub.20-alkyl, C.sub.2 C.sub.20-alkenyl, C.sub.4 C.sub.7-cycloalkyl, which in addition can contain an oxygen atom in the ring, aryl, C.sub.7 C.sub.20-aralkyl, C.sub.1 C.sub.20-acyl, aroyl, C.sub.1 C.sub.20-alkoxycarbonyl, C.sub.1 C.sub.20-alkylsulfonyl as well as arylsulfonyl can be cited.

As alkyl-, silyl- and acyl radicals for the protective groups PG, especially the radicals that are known to one skilled in the art are considered. Preferred are the alkyl or silyl radicals that can be easily cleaved from the corresponding alkyl and silyl ethers, such as, for example, the methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert.-butyldimethylsilyl, tert.-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl, benzyl, para-nitrobenzyl, and para-methoxybenzyl radicals, as well as alkylsulfonyl and arylsulfonyl radicals. As an alkoxycarbonyl radical, e.g., trichloroethyloxycarbonyl (Troc) is suitable. As an acyl radical, e.g., formyl, acetyl, propionyl, isopropionyl, trichloromethylcarbonyl, pivalyl, butyryl or benzoyl, which radical can be substituted with an amino and/or hydroxy group, is suitable.

As amino protective groups PG, the radicals that are known to one skilled in the art are suitable. For example, the Alloc, Boc, Z, benzyl, f-Moc, Troc, stabase or benzostabase group can be mentioned.

As halogen atoms, fluorine, chlorine, bromine or iodine can be considered.

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

The C.sub.2 C.sub.10-alkylene-.alpha.,.omega.-dioxy group that is possible for X is preferably an ethylene ketal or neopentyl ketal group.

Preferred compounds of general formula I are those in which A-Y represents O--C(.dbd.O) or NR.sup.21--C(.dbd.O); D-E represents an H.sub.2C--CH.sub.2 group; G represents a CH.sub.2 group; Z represents an oxygen atom; R.sup.1a, R.sup.1b in each case represent C.sub.1 C.sub.10 alkyl or together a --CH.sub.2).sub.p group with p equal to 2 or 3 or 4; R.sup.2a, R.sup.2b, independently of one another, represent hydrogen, C.sub.1 C.sub.10 alkyl, C.sub.2 C.sub.10 alkenyl, or C.sub.2 C.sub.10 alkynyl; R.sup.3 represents hydrogen; R.sup.4a, R.sup.4b, independently of one another, represent hydrogen or C.sub.1 C.sub.10 alkyl; R.sup.5 represents hydrogen, or C.sub.1 C.sub.4 alkyl or CH.sub.2OH or CH.sub.2NH.sub.2 or CH.sub.2N(alkyl, acyl).sub.1,2 or CH.sub.2Hal; R.sup.6 and R.sup.7 together represent an additional bond or together an NH group or together an N-alkyl group or together a CH.sub.2 group or together an oxygen atom; W represents a group C(.dbd.X)R.sup.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 represents a CR.sup.10R.sup.11 group; R.sup.8 represents hydrogen or C.sub.1 C.sub.4 alkyl or a fluorine atom or a chlorine atom or a bromine atom; R.sup.10/R.sup.11 represent hydrogen/2-methylthiazol-4-yl or hydrogen/2-pyridyl or hydrogen/2-methyloxazol-4-yl or hydrogen/2-aminomethylthiazol-4-yl or hydrogen/2-aminomethyloxazol-4-yl or hydrogen/2-hydroxymethylthiazol-4-yl or hydrogen/2-hydroxymethyloxazol-4-yl.

As linkers of general formula (III), compounds are preferred in which V represents a bond or an aryl radical, o is equal to zero, and T represents an oxygen atom.

As linkers of general formula (III), in addition compounds are preferred in which V represents a bond or an aryl radical or a group

##STR00011## Q represents a bond or a group

##STR00012## and o is 0 to 4. Especially preferred are compounds of general formula (III), wherein V represents a bond or a group

##STR00013## Q represents a bond or a group

##STR00014## o is equal to 0, 2 or 3; s is equal to 1; and T is an oxygen atom.

As linkers of general formula (IV), compounds are preferred in which o is zero to four, and q is zero to three. Especially preferred are compounds of general formula (IV), wherein o is 0, 2 or 3; W.sup.1 is an oxygen atom; q is equal to 0; R.sup.22 is hydrogen, C.sub.1 C.sub.3 alkyl or aralkyl; R.sup.23 is hydrogen or C.sub.1 C.sub.3 alkyl; R.sup.24a is hydrogen or C.sub.1 C.sub.3 alkyl; R.sup.27 is fluorine, chlorine, CN, NO.sub.2, CO.sub.2R.sup.28 or OR.sup.28; R.sup.28 is hydrogen or C.sub.1 C.sub.5 alkyl; and U is oxygen, CHR.sup.22 or CHR.sup.22--NR.sup.23--C(.dbd.O)--.

As recombinant proteins for use as recognition units, for example, binding regions derived from antibodies, so-called CDRs, are suitable.

As framework structures for use as recognition units, for example, high-molecular structures that are not derived from antibodies are suitable. For example, structures of the fibronectin type 3 and of crystallins can be mentioned.

As fragments of monoclonal antibodies for use as recognition units, for example, single-chain Fv, Fab, F(ab).sub.2 as well as recombinant multimers can be mentioned.

As preferred recognition units, those are considered that are suitable for, for example, the recognition and/or diagnosis and/or therapy of solid tumors and malignant diseases of the hematopoietic system.

As recognition units that are additionally preferred, those are considered that allow a selective recognition of the disease-specific vascular system, preferably of the angiogenesis.

Table 1 cites examples of especially preferred recognition units for treating solid tumors.

TABLE-US-00001 TABLE 1 Antigen Identity/ Monoclonal Tumor Characteristics Antibodies References Gynecol. (GY) CA 125' > 200 kD OC 125 Kabawat et al., 1983; mucin GP Szymendera, 1986 Ovarian 80 Kd GP OC 133 Masuko et al., Cancer Res, 1984 Ovarian `SGA` 360 Kd GP OMI de Krester et al., 1986 Ovarian High M.sub.r mucin Mo v1 Miotti et al., Cancer Res, 1985 Ovarian High M.sub.r mucin/ Mo v2 Miotti et al., Cancer Res, glycolipid 1985 Ovarian NS 3C2 Tsuji et al., Cancer Res, 1985 Ovarian NS 4C7 Tsuji et al., Cancer Res, 1985 Ovarian High M.sub.r mucin ID3 Gangopadhyay et al., 1985 Ovarian High M.sub.r mucin DU-PAN-2 Lan et al., 1985 GY 7700 Kd GP F 36/22 Croghan et al., 1984 Ovarian `gp 68` 48 Kd GP 4F.sub.7/7A.sub.10 Bhattacharya et al., 1984 GY 40, 42 kD GP OV-TL3 Poels et al., 1986 GY `TAG-72` High M.sub.r B72.3 Thor et al., 1986 mucin Ovarian 300 400 Kd GP DF.sub.3 Kufe et al., 1984 Ovarian 60 Kd GP 2C.sub.8/2F.sub.7 Bhattacharya et al., 1985 GY 105 Kd GP MF 116 Mattes et al., 1984 Ovarian 38 40 kD GP Mov18 Miotti et al., 1987 GY `CEA` 180 Kd GP CEA 11-H5 Wagener et al., 1984 Ovarian CA 19-9 or GICA CA 19-9 (1116NS Atkinson et al., 1982 19-9) Ovarian `FLAP` 67 Kd GP H17-E2 McDicken et al., 1985 Ovarian 72 Kd 791T/36 Perkins et al., 1985 Ovarian 69 Kd PLAP NDOG.sub.2 Sunderland et al., 1984 Ovarian unknown M.sub.r PLAP H317 Johnson et al., 1981 Ovarian p185.sup.HER2 4D5, 3H4, 7C2, Shepard et al., 1991 6E9, 2C4, 7F3, 2H11, 3E8, 5B8, 7D3, SB8 Uterus, Ovary HMFG-2 HMFG2 Epenetos et al., 1982 GY HMFG-2 3.14.A3 Burchell et al., 1983 Breast 330 450 Kd GP DF3 Hayes et al., 1985 Breast NS NCRC-11 Ellis et al., 1984 Breast 37 kD 3C6F9 Mandeville et al., 1987 Breast NS MBE6 Teramoto et al., 1982 Breast NS CLNH5 Glassy et al., 1983 Breast 47 Kd GP MAC 40/43 Kjeldsen et al., 1986 Breast High M.sub.r GP EMA Sloane et al., 1981 Breast High M.sub.r GP HMFG1 HFMG2 Arklie et al., 1981 Breast NS 3.15.C3 Arklie et al., 1981 Breast NS M3, M8, M24 Foster et al., 1982 Breast 1 (Ma) Blood Group M18 Foster et al., 1984 Ags Breast NS 67-D-11 Rasmussen et at., 1982 Breast Estrogen Receptor D547Sp, D75P3, Kinsel et al., 1989 H222 Breast EGF Receptor Anti EGF Sainsbury et al., 1985 Breast Laminine Receptor LR-3 Horan Hand et al., 1985 Breast erb B-2 p185 TA1 Gusterson et al., 1988 Breast NS H59 Hendler et al., 1981 Breast 126 Kd GP 10-3D-2 Soule et al., 1983 Breast NS HmAB1, 2 Imam et al., 1984; Schlom et al., 1985 Breast NS MBR 1, 2, 3 Menard et al., 1983 Breast 95 Kd 24-17-1 Thompson et al., 1983 Breast 100 Kd 24-17-2 (3E1-2) Croghan et al., 1983 Breast NS F36/22.M7/105 Croghan et al., 1984 Breast 24 Kd C11, G3, H7 Adams et al., 1983 Breast 90 Kd GP B6-2 Colcher et al., 1981 Breast CEA & 180 Kd GP B1-1 Colcher et al., 1983 Breast Colon & pancreas, Cam 17-1 Imperial Cancer mucin-like Research Technology Ca 19-9 MAb listing Breast Milk mucin, nuclear SM3 Imperial Cancer protein Research Technology Mab listing Breast Milk mucin, nuclear SM4 Imperial Cancer protein Research Technology Mab listing Breast Affinity-purified milk C-Mul (566) Imperial Cancer mucin Research Technology Mab listing Breast p185.sup.HER2 4D5 3H4, 7C2, Shepard et al., 1991 6E9, 2C4, 7F3, 2H11, 3E8, 5B8, 7D3, 5B8 Breast CA 125 > 200 Kd GP OC 125 Kabawat et al., 1985 Breast High M.sub.r mucin/ MO v2 Miotti et al., 1985 glycolipid Breast High M.sub.r mucin DU-PAN-2 Lan et al., 1984 Breast `gp48` 48 Kd GP 4F.sub.7/7A.sub.10 Bhattacharya et al., 1984 Breast 300 400 Kd GP DF.sub.3 Kufe et al., 1984 Breast `TAG-72` high M.sub.r B72-3 Thor et al., 1986 mucin Breast `CEA` 180 Kd GP cccccCEA 11 Wagener et al., 1984 Breast `PLAP` 67 Kd GP H17-E2 McDicken et al., 1985 Breast HMFG-2 > 400 Kd GP 3-14-A3 Burchell et al., 1983 Breast NS FO23C5 Riva et al., 1988 Colorectal TAG-72 High M.sub.r B72-3 Colcher et al., 1987 mucin Colorectal GP37 (17-1A) 1038-17- Paul et al., 1986 1A Colorectal Surface GP CO17-1A LoBuglio et al., 1988 Colorectal CEA ZCE-025 Patt et al., 1988 Colorectal CEA AB2 Griffin et al., 1988a Colorectal Cell surface AG HT-29-15 Cohn et al., 1987 Colorectal Secretory epithelium 250-30.6 Leydem et al., 1986 Colorectal Surface glycoprotein 44X14 Gallagher et al., 1986 Colorectal NS A7 Takahashi et al., 1988 Colorectal NS GA73-3 Munz et al., 1986 Colorectal NS 791T/36 Farrans et al., 1982 Colorectal Cell Membrane & 28A32 Smith et al., 1987 Cytoplasmatic Ag Colorectal CEA & Vindesin 28.19.8 Corvalen, 1987 Colorectal gp72 X MMCO-791 Byers et al., 1987 Colorectal high M.sub.r mucin DU-PAN-2 Lan et al., 1985 Colorectal high M.sub.r mucin ID.sub.3 Gangopadhyay et al., 1985 Colorectal CEA 180 Kd GP CEA 11-H5 Wagener et al., 1984 Colorectal 60 Kd GP 2C.sub.8/2F.sub.7 Bhattacharya et al., 1985 Colorectal CA-19-9 (or GICA) CA-19-9 Atkinson et al., 1982 (1116NS 19-9) Colorectal Lewis a PR5C5 Imperial Cancer Research Technology Mab Listing Colorectal Lewis a PR4D2 Imperial Cancer Research Technology Mab Listing Colorectal Colon mucus PR4D1 Imperial Cancer Research Technology Mab Listing Melanoma P97.sup.a 4-1 Woodbury et al., 1980 Melanoma P97.sup.a 8-2 M.sub.17 Brown, et al., 1981a Melanoma P97.sup.b 96-5 Brown, et al., 1981a Melanoma P97.sup.c 118-1, 133-2, Brown, et al., 1981a (113-2) Melanoma P97.sup.c L.sub.1, L.sub.10, R.sub.10 Brown et al., 1981b (R.sub.19) Melanoma P97.sup.d I.sub.12 Brown et al., 1981b Melanoma P97.sup.e K.sub.5 Brown et al., 1981b Melanoma P155 6-1 Loop et al., 1981 Melanoma G.sub.D3 disialogan- R24 Dippold et al., 1980 gliosides Melanoma P210, p60, p250 5-1 Loop et al., 1981 Melanoma P280 p440 225.28S Wilson et al., 1981 Melanoma GP 94, 75, 70 & 25 465.12S Wilson et al., 1981 Melanoma P240 P250, P450 9-2-27 Reisfeld et al., 1982 Melanoma 100, 77, 75 Kd F11 Chee et al., 1982 Melanoma 94 Kd 376.96S Imai et al., 1982 Melanoma 4 GP Chains 465.12S Imai et al., 1982; Wilson et al., 1981 Melanoma GP 74 15-75 Johnson & Reithmuller, 1982 Melanoma GP 49 15-95 Johnson & Reithmuller, 1982 Melanoma 230 Kd Mel-14 Carrel et al., 1982 Melanoma 92 Kd Mel-12 Carrel et al., 1982 Melanoma 70 Kd Me3-TB7 Carrel et al., 1:387, 1982 Melanoma HMW MAA similar to 225.28SD Kantor et al., 1982 9-2-27 AG Melanoma HMW MAA similar to 763.24TS Kantor et al., 1982 9-2-27 AG Melanoma GP95 similar to 376- 705F6 Stuhlmiller et al., 1982 96S 465-12S Melanoma GP125 436910 Saxton et al., 1982 Melanoma CD41 M148 Imperial Cancer Research Technology Mab listing Gastrointestinal high M.sub.r mucin ID3 Gangopadhyay et al., (GI) 1985 Gallbladder, high M.sub.r mucin DU-PAN-2 Lan et al., 1985 Pancreas, Stomach Pancreas NS OV-TL3 Poels et al., 1984 Pancreas, `TAG-72` high M.sub.r B72-3 Thor et al., 1986 Stomach, mucin Esophagus Stomach `CEA` 180 Kd GP CEA 11-H5 Wagener et al., 1984 Pancreas HMFG-2 > 400 Kd GP 3-14-A3 Burchell et al., 1983 GI NS C COLI Lemkin et al., 1984 Pancreas, CA 19-9 (or GICA) CA-19-9 Szymendera, 1986 Stomach (1116NS 19-9) and CA50 Pancreas CA125 GP OC125 Szymendera, 1986 Lung p185.sup.HER2 Shepard et al., 1991 Non-small-cell 4D5, 3H4, 7C2, lung cancer 6E9, 2C4, 7F3, (NSCLC) 2H11, 3E8, 5B8, 7D3, SB8 NSCLC high M.sub.r MO v2 Miotti et al., 1985 mucin/glycolipid NSCLC `TAG-72` high M.sub.r B72-3 Thor et al., 1986 mucin NSCLC High M.sub.r mucin DU-PAN-2 Lan et al., 1985 NSCLC `CEA` 180 kD GP CEA 11-H5 Wagener et al., 1984 Malignant Cytoplastic antigen that MUG 8-22 Stavrou, 1990 Glioma consists of 85HG-22 cells Malignant Cell surface Ag that MUC 2-63 Stavrou, 1990 Glioma consists of 85HG-\63 cells Malignant Cell surface Ag that MUC 2-39 Stavrou, 1990 Glioma consists of 86HG-39 cells Malignant Cell surface Ag that MUG 7-39 Stavrou, 1990 Glioma consists of 86HG-39 cells GC, Other P53 PAb 240, PAb Imperial Cancer 246, PAb 1801 Research Technology MaB Listing Small, Round- Neural cell adhesion ERIC-1 Imperial Cancer Cell Tumors molecules Research Technology MaB Listing Medulloblastomas, M148 Imperial Cancer Neuroblastomas, Research Technology Rhabdomyosarcomas MaB Listing Neuroblastomas FMH25 Imperial Cancer Research Technology MaB Listing Kidneys & P155 6-1 Loop et al., 1981 Glioblastomas Bladders & "Ca Antigen" 350 390 kD CA1 Ashall et al., 1982 Laryngeal Tumors Neuroblastoma GD2 3F8 Cheung et al., 1986 Prostate Gp48 48 kD GP 4F.sub.7/7A.sub.10 Bhattacharya et al., 1984 Prostate 60 kD GP 2C.sub.8/2F.sub.7 Bhattacharya et al., 1985 Thyroid `CEA` 180 kD GP CEA 11-H5 Wagener et al., 1984 Prostata Neurocellin-2 (NC-2), 2H8, 10G6 Berlex TMEFF2, TENB2, tomoregulin, TMP-2

As especially preferred recognition units for treating hematological tumors, antibodies or antibody fragments, such as CD19, CD20, CD40, CD22, CD25, CD5, CD52, CD10, CD2, CD7, CD33, CD38, CD40, CD72, CD4, CD21, CD5, CD37 and CD30, can also be mentioned.

As especially preferred recognition units for anti-angiogenic therapy, antibodies or fragments thereof, such as VCAM, CD31, ELAM, endoglin, VEGFRI/II, .alpha..sub.v.beta..sub.3, Tie1/2, TES23 (CD44ex6), phosphatidylserine, PSMA, VEGFR/VEGF complex or ED-B-fibronectin, can be mentioned.

The compounds that are mentioned below are especially preferred according to the invention as effector elements: (4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methy- l-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-y- l)-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-vin- yl]-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]heptad- ecane-5,9-dione, (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-thiazo- l-4-yl)-1-methyl-vinyl]-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0- ]heptadecane-5,9-dione, (1S,3S(E),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-thiazol-4-yl)-1-methyl-- vinyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]h- eptadecane-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-y- l)-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-meth- yl-vinyl]-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en- e-2,6-dione, (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetrameth- yl-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-thiazo- l-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-fluor- o-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-y- l)-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-vin- yl]-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]heptad- ecane-5,9-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-thiazo- 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-thiazol-4-yl)-1-fluoro-- vinyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]h- eptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-chlor- o-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-y- l)-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-vin- yl]-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]heptad- ecane-5,9-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-thiazo- l-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]h- eptadecane-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-y- l)-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-fluo- ro-vinyl]-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en- e-2,6-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetrameth- yl-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-thiazo- l-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-fluoro-- 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-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-y- l)-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-chlo- ro-vinyl]-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-en- e-2,6-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16-tetrameth- yl-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-thiazo- l-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-methy- l-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-di- one, (4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-1- 6-[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-tetrameth- yl-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-1- 6-[1-fluoro-2-(2-pyridyl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,1-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1- -fluoro-2-(2-pyridyl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptadecane-5,9-dio- ne, (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-ch- loro-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-di- one, (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-1- 6-[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-tetrameth- yl-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-tetrame- thyl-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-tetrameth- yl-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-1- 6-[1-methyl-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dio- ne, (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-dio- ne, (4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-Aminomethyl-oxazol-4-yl)-1-methyl-vi- nyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione- , (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-- [1-methyl-2-(2-methyl-oxazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptad- ecane-5,9-dione, (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-oxazol- -4-yl)-1-methyl-vinyl]-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]- heptadecane-5,9-dione, (1S,3S(E),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-1-methyl-v- inyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]he- ptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[1- -methyl-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(E))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4-yl- )-1-methyl-vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-- dione, (4S,7R,8S,9S,13Z,16S(E))-16-[2-(2-Aminomethyl-oxazol-4-yl)-1-methyl- -vinyl]-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-- 2,6-dione, (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16- -tetramethyl-3-[1-methyl-2-(2-methyl-oxazol-4-yl)-vinyl]-4,17-dioxa-bicycl- o[14.1.0]heptadecane-5,9-dione, (1S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-oxazol- -4-yl)-1-methyl-vinyl]-10-ethyl-8,8,12,16-tetramethyl-4,17-dioxa-bicyclo[1- 4.1.0]heptadecane-5,9-dione, (1S,3S(E),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-1-methyl-v- inyl]-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-fluor- o-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-oxazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptade- cane-5,9-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-3-[2-(2-hydroxymethyl-oxazol- -4-yl)-1-fluoro-vinyl]-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]- heptadecane-5,9-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-1-fluoro-v- inyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]he- ptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16-[1-chlor- o-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4-yl- )-1-chloro-vinyl]-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-oxazol-4-yl)-1-chloro-vinyl- ]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-oxacyclohexadec-13-ene-2,6-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[- 1-chloro-2-(2-methyl-oxazol-4-yl)-vinyl]-4,17-dioxa-bicyclo[14.1.0]heptade- cane-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-v- inyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa-bicyclo[14.1.0]he- ptadecane-5,9-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-7-ethyl-5,5,9,13-tetramethyl-16-[1- -fluoro-2-(2-methyl-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4-yl- )-1-fluoro-vinyl]-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-2,6-- dione, (4S,7R,8S,9S,13Z,16S(Z))-16-[2-(2-Aminomethyl-oxazol-4-yl)-1-fluoro- -vinyl]-4,8-dihydroxy-7-ethyl-5,5,9,13-tetramethyl-oxacyclohexadec-13-ene-- 2,6-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-ethyl-8,8,12,16- -tetramethyl-3-[1-fluoro-2-(2-methyl-oxazol-4-yl)-vinyl]-4,17-dioxa-bicycl- o[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[1- 4.1.0]heptadecane-5,9-dione, (1S,3S(Z),7S,10R,11S,12S,16R)-3-[2-(2-Aminomethyl-oxazol-4-yl)-1-fluoro-v- inyl]-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-oxazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione, (4S,7R,8S,9S,13Z,16S(Z))-4,8-Dihydroxy-16-[2-(2-hydroxymethyl-oxazol-4-yl- )-1-chloro-vinyl]-7-ethyl-5