CA2360452A1 - C-21 modified epothilones - Google Patents

C-21 modified epothilones Download PDF

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Publication number
CA2360452A1
CA2360452A1 CA002360452A CA2360452A CA2360452A1 CA 2360452 A1 CA2360452 A1 CA 2360452A1 CA 002360452 A CA002360452 A CA 002360452A CA 2360452 A CA2360452 A CA 2360452A CA 2360452 A1 CA2360452 A1 CA 2360452A1
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Prior art keywords
group
dihydroxy
dione
thiazolyl
methyl
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CA002360452A
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French (fr)
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CA2360452C (en
Inventor
Gerhard Hoefle
Nicole Glaser
Thomas Leibold
Gregory Vite
Soong-Hoon Kim
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Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
Bristol Myers Squibb Co
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Priority claimed from DE1999107588 external-priority patent/DE19907588A1/en
Priority claimed from DE1999130111 external-priority patent/DE19930111A1/en
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10Antimycotics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/04Antineoplastic agents specific for metastasis
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D493/00Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04Ortho-condensed systems

Abstract

The invention is concerned with epothilones in which the thiazole substituent has been modified, with methods for their preparation and with antifungal or therapeutic agents which contain these epothilones.

Claims (30)

1. Compound having the general formula I
where:
P-Q is a C, C double bond or an epoxide;
G is R is selected from the group of H, alkyl, and substituted alkyl;
R1 is selected from the group consisting of R2 is G1 is selected from the group of H, halogen, CN, alkyl and substituted alkyl;
G2 is selected from the group of H, alkyl, and substituted alkyl;

G3 is selected from the group of O, S, and NZ1;
G4 is selected from the group of H, alkyl, substituted alkyl, OZ2, NZ2Z3, Z2C=O, ZSO2, and optionally substituted glycosyl;

G5 is selected from the group of halogen, N3, NCS, SH, CN, NC, N (Z1)3+ and heteroaryl;
G6 is selected from the group of H, alkyl, substituted alkyl, CF3, OZ5, SZ5, and NZ5Z6;
G7 is CZ7 or N;
G8 is selected from the group of H, halogen, alkyl, substituted alkyl, OZ10, SZ10, NZ10Z11;
G9 is selected from the group of O, S, -NH-NH- and -N=N-;
G10 is N or CZ12 G11 is selected from the group of H2N, substituted H2N, alkyl, substituted alkyl, aryl, and substituted aryl;
Z1, Z6, Z9, and Z11 are independently selected from the group H, alkyl, substituted alkyl, acyl, and substituted acyl;
Z2 is selected from the group of H, alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;
Z3, Z5, Z8, and Z10 are independently selected from the group H, alkyl, substituted alkyl, acyl, substituted acyl, aryl, and substituted aryl;
Z4 is selected from the group of alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;
Z7 is selected from the group of H, halogen, alkyl, substituted alkyl, aryl, substituted aryl, OZ8, SZ8, and NZ8Z9; and Z12 is selected from the group of H, halogen, alkyl, substituted alkyl, aryl, and substituted aryl;
with the proviso that when R1 is G1, G2, G3 and G4 cannot simultaneously have the following meanings:
G1 and G2 = H, G3 - O and G4 - H or Z2C=O where Z2 -alkyl group.
2. Compound according to claim 1 having general formula Ia where the symbols have the following meaning:
P-Q is a C,C double bond or an epoxide, R is a H atom or a methyl group, G1 is an H atom, an alkyl group, a substituted alkyl group or a halogen atom, G2 is an H atom, an alkyl group or a substituted alkyl group, G3 is an O atom, an S atom or an NZ1 group with Z1 being an H atom, an alkyl group, a substituted alkyl group, an acyl group, or a substituted acyl group, and G4 is an H atom, an alkyl group, a substituted alkyl group, an OZ2 group, an NZ2Z3 group, a Z2C=O group, a Z4SO2 group or an optionally substituted glycosyl group with Z2 being a H atom, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group or a heterocyclic group, Z3 an H atom, an alkyl group, a substituted alkyl group, an acyl group or a substituted acyl group, and Z4 an alkyl, a substituted alkyl, an aryl, a substituted aryl or a heterocyclic group, with the proviso that G1, G2, G3 and G9 cannot have simultaneously the following meanings: G1 and G2 = H atom, G3 = O atom and G4 - H atom or Z2C=O with Z2 - alkyl group.
3. Compound according to claim 2, wherein G3 is an O
atom.
4. Compound according to claim 2, wherein G3 is a S
atom.
5. Compound according to claim 2, wherein G3 is NZ1.
6. Compound according to claim 1 having general formula Ib where the symbols have the following meaning:
P-Q is a C,C double bond or an epoxide, R is a H atom or a methyl group, G1 is a H atom, an alkyl group, a substituted alkyl group or a halogen atom, G2 is a H atom, an alkyl group or a substituted alkyl group, and G5 is a halogen atom, an N3 group, an NCS group, an SH
group, a CN group, an NC group or a heterocyclic group.
7. Compound according to claim 6, wherein G5 is an N3 group.
8. Compound according to claim 6, wherein G5 is an NCS
group.
9. Compound according to claim 6, wherein G5 is an SH
group.
10. Compound according to claim 6, wherein G5 is a CN
group.
11. Compound according to claim 6, wherein G5 is an NC
group.
12. Compound according to claim 6, wherein G5 is a heterocyclic group.
13. Compound according to claim 1 having general formula IIa where the symbols have the following meaning:
P-Q is a C,C double bond or an epoxide, R is a H atom or a methyl group, G6 is a H atom, an alkyl group, a substituted alkyl group or a CF3, OZ5, SZ5 or NZ5Z6 group with Z5 being a H atom, an alkyl group, a substituted alkyl group, an acyl group or a substituted acyl group, and Z6 being a H atom, an alkyl group or a substituted alkyl group, G7 is a CZ7 group or an N atom with Z7 being a H or halogen atom, an alkyl group, a substituted alkyl group, an aryl group, or a substituted aryl group, or an OZ8, SZ8 or NZ8Z9 group with Z8 being an H atom or an alkyl group, a substituted alkyl group, an acyl group or a substituted acyl group, and Z9 being a H atom, an alkyl group or a substituted alkyl group, and G8 being a H or a halogen atom, an alkyl group, a substituted alkyl group or an OZ10, SZ10 or NZ10Z11 group with Z10 being a H atom, an alkyl group, a substituted alkyl group, an acyl group, a substituted acyl group, an aryl group, or a substituted aryl group, and Z11 being a H atom, an alkyl group, a substituted alkyl group, an aryl group, or a substituted acyl group.
14. Compound according to claim 1 having general formula IIb where the symbols have the following meaning:

P-Q is a C,C double bond or an epoxide, R is a H atom or a methyl group, G6 is a H atom, an alkyl group, a substituted alkyl group or a CF3, OZ5, SZ5 or NZ5Z6 group with Z5 being a H atom, an alkyl group, a substituted alkyl group, an acyl group or a substituted acyl group, and Z6 being a H atom, an alkyl group or a substituted alkyl group, and G9 is an O or S atom or an -N=N- group.
15. Compound according to claim 14, wherein G9 is an O
atom.
16. Compound according to claim 1 having general formula III

where the symbols have the following meaning:
P-Q is a C,C double bond or an epoxide, R is a H atom or a methyl group, G10 is an N atom or a CZ12 group with Z12 being a H or halogen atom, an alkyl group, a substituted alkyl group, an aryl group, or a substituted aryl group.
17. Compound according to claim 16, wherein G10 is an N
atom.
18. Compound according to claim 16, wherein G10 is a CZ12 group.
19. Compound according to claim 1 having general formula IV
where the symbols have the following meaning:
P-Q is a C,C double bond or an epoxide, R is a H atom or a methyl group, and G11 is an H2N group, a substituted H2N group, an alkyl group, a substituted alkyl group, an aryl group or a substituted aryl group.
20. Compound selected from the group consisting of:
[1S-[1R~,3R~(E),7R~,10S~,11R~,12R~,16S~]]-3-[2-[2-(Azidomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R~,3R~(E),7R~,10S~,11R~,12R~,16S~]]-3-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R~,3R~(E),7R~,10S~,11R~,12R~,16S~]]-3-[2-[2-[[[(1,1-Dimethylethoxy)carbonyl]amino]methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[4S-[4R~,7S~,8R~,9R~,15R~(E)]]-16-[2-[2-[[[(1,1-Dimethylethoxy)carbonyl]amino]methyl]-4-thiazolyl]-1-methyl-ethenyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13(Z)-cyclohexadecene-2,6-dione;
[4S-[4R~,7S~,8R~,9R~,15R~(E)]]-16-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13(Z)-cyclohexadecene-2,6-dione;
[1S-[1R~,3R~(E),7R~,10S~,11R~,12R~,16S~]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(pentanoyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R~,3R~(E),7R~,10S~,11R~,12R~,16S~]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(naphthoyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R~,3R~(E),7R~,10S~,11R~,12R~,16S~]]-7,11-Dihydroxy-3-[2-[2-[[(2-methoxyethoxy)acetyloxy]methyl]-1-methyl-4-thiazolyl]ethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R~,3R~(E),7R~,10S~,11R~,12R~,165~]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(N-propionylamino)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R~,3R~(E),7R~,10S~,11R~,12R~,16S~]]-3-[2-(3-Acetyl-2,3-dihydro-2-methylene-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione, N-oxide;
[1S-[1R~,3R~(E),7R~,10S~,11R~,12R~,16S~]]-7,11-Dihydroxy-3-[2-[2-(methoxymethyl)-4-thiazolyl]-1-methylethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R~,3R~(E),7R~,10S~,11R~,12R~,16S~]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-(phenoxymethyl)-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R~,3R~(E),7R~,10S~,11R~,12R~,16S~]]-3-[2-[2-[(Ethylthio)methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R~,3R~(E),7R~,10S~,11R~,12R~,16S~]]-3-[2-[2-(Ethoxymethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R~,3R~(E),7R~,10S~,11R~,12R~,16S~]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(2,3,4,6-tetraacetyl-alpha-glucosyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R~,3R~(E),7R~,10S~,11R~,12R~,165~]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(2',3',4',6'-tetraacetyl-beta-glucosyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R~,3R~(E),7R~,10S~,11R~,12R~,16S~]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(6'-acetyl-alpha-glucosyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R~,3R~(E),7R~,10S~,11R~,12R~,16S~]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-[(p-toluenesulfonyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R~,3~R~(E),7R~,10S~,11R~,12R~,16S~]]-3-[2-[2-(Bromomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(5-Bromo-2-methyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Cyanomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-16-[2-[2-(Cyanomethyl)-4-thiazolyl]-1-methylethenyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13(Z)-cyclohexadecene-2,6-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(1H-imidazol-1-ylmethyl)-4-thiazolyl]-1-methylethenyl]-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Formyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Formyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Ethenyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(methoxyimino)-4-thiazolyl]-1-methylethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[[(phenylmethyl)imino]methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,165*]]-3-[2-(2-Acetyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-oxiranyl-4-thiazolyl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(2-iodoethenyl)-4-thiazolyl]-1-methylethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Ethynyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,165*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-[(methylamino)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[[[2-(Dimethylamino)ethyl]amino]methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[(Dimethylamino)methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[[Bis(2-methoxyethyl)amino]methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-[(4-methyl-1-piperazinyl)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-4-[2-(7,11-Dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecan-3-yl)-1-propenyl]-2-thiazolecarboxylic acid;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-4-[2-(7,11-Dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecan-3-yl)-1-propenyl]-2-thiazolecarboxylic acid methyl ester and the pharmaceutically acceptable salts, solvents and hydrates thereof.
21. Method for the preparation of a compound having formula 9, corresponding to general formula Ia, wherein G1 and G2 ar H atoms, G3 is NZ1, and Z1 and G4 are H atoms, wherein a compound having formula 4 or 5 is first activated and subsequently subjected to a nucleophilic displacement to obtain a compound having formula 7 wherein the resulting compound having formula 7 is reduced to form a compound having formula 9, where P-Q = CH=C or CH...C, where ... is a C-C single bond with an epoxide O bridge, R = a hydrogen atom or a methyl group and X = N3.
22. Method according to claim 21, wherein (i) the activation is carried out with TosHal (Hal = Cl, Br or I) and pyridine and the nucleophilic displacement with NaN3 or (ii) that activation and nucleophilic displacement. are carried out with diazabicycloundecene (DBU) and diphenylphosphoryl azide (DPPA).
23. Method according to claim 21, wherein the reduction is carried out (i) as a hydrogenation with the aid of a Lindlar catalyst or (ii) with a phosphine.
24. A pharmaceutical composition which comprises as active ingredient an amount of at least one compound selected from the group consisting of a compound of the general formula according to claim 1, a compound of formula Ia according to claim 2, a compound of formula Ib according to claim 6, a compound of formula IIa according to claim 13, a compound of formula IIb acccording to claim 14, a compound of formula III according to claim 16, a compound of formula IV according to claim 19 and a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients or diluents thereof.
25. A pharmaceutical composition of claim 24 which comprises as active ingredient an amount of at least one compound which is an anti-cancer or cytotoxic agent.
26. A pharmaceutical composition of claim 25 wherein the anti-cancer or cytotoxic agent is selected from the group consisting of [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Azidomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,165*]]-3-[2-[2-[[[(1,1-Dimethylethoxy)carbonyl]amino]methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-16-[2-[2-[[[(1,1-Dimethylethoxy)carbonyl]amino]methyl]-4-thiazolyl]-1-methyl-ethenyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13(Z)-cyclohexadecene-2,6-dione;
[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-16-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13(Z)-cyclohexadecene-2,6-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(pentanoyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione:
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(naphthoyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-[[(2-methoxyethoxy)acetyloxy]methyl]-1-methyl-4-thiazolyl]ethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(N-propionylamino)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(3-Acetyl-2,3-dihydro-2-methylene-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione, N-oxide;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(methoxymethyl)-4-thiazolyl]-1-methylethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-(phenoxymethyl)-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[(Ethylthio)methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Ethoxymethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(2,3,4,6-tetraacetyl-alpha-glucosyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(2',3',4',6'-tetraacetyl-beta-glucosyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(6'-acetyl-alpha-glucosyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,165*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-[(p-toluenesulfonyloxy)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Bromomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,165*]]-3-[2-(5-Bromo-2-methyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Cyanomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-16-[2-[2-(Cyanomethyl)-4-thiazolyl]-1-methylethenyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13(Z)-cyclohexadecene-2,6-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(1H-imidazol-1-ylmethyl)-4-thiazolyl]-1-methylethenyl]-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,165*]]-3-[2-(2-Formyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Formyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,165*]]-3-[2-(2-Ethenyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(methoxyimino)-4-thiazolyl]-1-methylethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,165*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[[(phenylmethyl)imino]methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Acetyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-oxiranyl-4-thiazolyl)ethenyl)-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3,[2-[2-(2-iodoethenyl)-4-thiazolyl]-1-methylethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione:
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Ethynyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-[(methylamino)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,165*]]-3-[2-[2-[[[2-(Dimethylamino)ethyl]amino]methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[(Dimethylamino)methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[[Bis(2-methoxyethyl)amino]methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-[(4-methyl-1-piperazinyl)methyl]-4-thiazolyl]ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;
[1S-(1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-4-[2-(7,11-Dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecan-3-yl)-1-propenyl]-2-thiazolecarboxylic acid;
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-4-[2-(7,11-Dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecan-3-yl)-1-propenyl]-2-thiazolecarboxylic acid methyl ester and the pharmaceutically acceptable salts, solvents and hydrates thereof.
27. Use of a pharmaceutical composition according to claim 24 for treating cancer or other proliferative diseases.
28. Use of a pharmaceutical composition according to claim 24 for inhibiting angiogenesis.
29. Use of a pharmaceutical composition according to claim 24 for inducing apoptosis.
30. Use of a pharmaceutical composition for treating cancer or other proliferative diseases according to claim 27 simultaneously or sequentially with another therapeutic agent useful for the treatment of cancer or other proliferative diseases.
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