WO2000049019A2 - Novel epothilone derivatives, method for producing them and their pharmaceutical use - Google Patents

Abstract

The invention relates to novel epothilone derivatives of general formula (I), wherein the substituents Y, Z, R?1a, R1b, R2a, R2b¿, G'-G-E-E', R?5, R6, R7, R8, R14¿ and X have the meanings specified in the description. The novel compounds interact with tubulin by stabilising the microtubuli which are formed. They are able to influence the cell division phase-specifically and are suitable for treating malignant tumours such as cancers of the ovaries, stomach, colon, glands, breasts, lungs and head and neck, malignant melanoma and acute lymphocytic and myelocytic leukaemia. The compounds are also suitable for anti-angiogenesis therapy and for treating chronic inflammatory diseases (psoriasis, arthritis) and can be deposited on or in polymer materials in order to prevent uncontrolled cell proliferations on medical implants and to improve the compatibility thereof. The inventive compounds can be used alone or in combination with other principles and classes of substances that can be used in the therapy of tumours in order to achieve additive or synergistic effects.

Description

 New epothiion derivatives, processes for their preparation and their pharmaceutical use

By Höfle et al. the cytotoxic effects of the natural substances epothilone A (R hydrogen) and epothilon B (R = methyl)

Epothilon A (R = H), Epothilon B (R=CH3)

Epothilone A (R = H), epothilone B (R = CH3)

e.g. in Angew. Chem. 1996, 108, 1671-1673. Because of the in vitro selectivity towards breast and intestinal cell lines and their significantly higher activity against P-glycoprotein-forming, multi-resistant tumor lines compared to Taxol as well as their improved physical properties compared to Taxol, e.g. a 30 times higher water solubility, this is new Structural class of particular interest for the development of a drug for the treatment of malignant tumors.

The natural products are not sufficiently stable both chemically and metabolically for drug development. Modifications to the natural product are necessary to eliminate these disadvantages. Such modifications are only possible in a totally synthetic way and presuppose synthesis strategies that enable a broad modification of the natural product. The aim of the structural changes is also to increase the therapeutic range. This can be achieved by improving the selectivity of the action and / or increasing the potency and / or reducing undesirable toxic side effects, as described in Proc. Natl. Acad. Be. USA 1998, 95, 9642-9647 are described.

The total synthesis of epothilone A is by Schinzer et al. in Chem. Eur. J. 1996, 2, No. 11, 1477-1482 and in Angew. Chem. 1997, 109, No. 5, pp. 543-544). Epothilone derivatives have already been described by Höfle et aJ. described in WO 97/19086. These derivatives were made from natural epothilone A or B. Another synthesis of epothilone and epothilone derivatives was by Nicolaou et al. in Angew. Chem. 1997, 109, No. 1/2, pp. 170-172. The synthesis of epothilones A and B and some epothilone analogues was described in Nature, Vol. 387, 1997, pp. 268-272, the synthesis of epothilone A and its derivatives in J. Am. Chem. Soα, Vol. 119, No. 34, 1997, pp. 7960-7973 and the synthesis of epothilones A and B and some epothilone analogues in J. Am. Chem. Soc, Vol. 119, No. 34, 1997, pp. 7974-7991 also by Nicolaou et al. described.

Nicolaou et al. describe in Angew. Chem. 1997, 109, No. 19, pp. 2181-2187 the preparation of epothilone A analogues by means of combinatorial solid phase synthesis. Some epothilone B analogues are also described there.

The object of the present invention is to provide new epothilone derivatives which are sufficiently stable both chemically and metabolically for drug development and which have a therapeutic breadth, their selectivity of action and / or undesirable toxic side effects and / or their Potency are superior to natural derivatives.

The present invention describes the new epothilone derivatives of the general formula I

wherein

Rl a _τ p1 b are identical or different and are hydrogen, Ci-Ci Q-alkyl, aryl, C7-C20-aralkyl, or together a - (CH2) m group with m = 1, 2, 3, 4 or 5, a - (CH2) -O- (CH2) group, R ^2a , R ² b are the same or different and are hydrogen, C 1 -C 8 -alkyl, aryl,

C7-C20-aralkyl or together a - (CH2) n group with n = 2, 3, 4 or 5,

G'-G-E-E 'a group

R3a is hydrogen, C 1 -C 8 alkyl, aryl, C 1 -C 4 aralkyl,

R14 hydrogen, OR ¹ a, shark, OSO ₂ R ^14b ,

_R 3b OPG ¹ or R3b_ Rl4a together form a bond,

² H the hydrogen isotope deuterium,

3H the hydrogen isotope tritium,

R ⁴ is hydrogen, C ^«| -C- | o-alkyl, aryl, C7-C20-ralkyl,

R ^{5 is} hydrogen, C- | -C <ιo-alkyl, aryl, C7-C20- ralkyl, (CH2) _S -A where s is 1, 2, 3 or 4,

A represents OR ²² or shark, R ^{22 represents} hydrogen or PG ⁴ , R6, R ⁷ each represent a hydrogen atom, together an additional bond or an oxygen atom, R ^{8 represents} hydrogen, C- | -C20-al yl, aryl, C7-C20 - Ralkyl, which can all be substituted, X is an oxygen atom, two alkoxy groups OR ²³ , a C2-C <| rj-alkylene-α, ω-dioxy group, which can be straight-chain or branched, H / OR ⁹ or a group CR ^ 0R11, where

R ^{23 represents} a C 1 -C 20 -alkyl radical,

R ^{9 represents} hydrogen or a protective group PG ^X ,

R10, R ¹ 1 are the same or different and represent hydrogen, a C 1 -C 20 -alkyl, aryl, C7-C20 aralkyl radical or R10 and R ¹ 1 together with the methylene carbon atom together for a 5- to 7-membered carbocyclic ring stand, Y one oxygen atom or two hydrogen atoms, Z one oxygen atom or H / OR ¹² , in which

R ^{12 is} hydrogen or a protective group PG ^Z.

The presentation of the new epothilone derivatives is based on the linkage of three partial fragments A, B and C. This method is used in the production of other epothilone derivatives which differ from the compounds according to the invention in the section from carbon atom 7 to carbon atom 10 in DE 197 51 200.3, filing date November 13, 1997 and in the corresponding PCT / EP98 / 05064. The interfaces are as indicated in the general formula I '.

A represents a C1-C6 fragment (epothilone counting) of the general formula

A, in which

Ria ', Rl b', R2a ' _unc | R ² 'already mentioned for R ^a , R ^b , R ^2a and R ^2b

Have meanings and R13 CH ₂ OR ^{1 a} , CH ₂ -Hal, CHO, CO ₂ R ^{1 3b} , COHal,

R1 ⁴ hydrogen, ORl ^a , shark, OSO ₂ R ^14b , Rl ^3a , Rl ^4a hydrogen, Sθ2-alkyl, SO2-A17I, Sθ2-aralkyl or together a - (CH2) ₀ group or together a CR ^{1 5a} R ^{1 5b} group, Rl3b ₇ Rl4b hydrogen, Ci ^ r _j alkyl, aryl, C 1 -C 20 aralkyl, Rl 5a _ι Rl 5b are the same or different and are hydrogen, CjC iQ alkyl, aryl,

C7-C20-aralkyl, or together a - (CH2) q group, Hal is halo, o 2 to 4, q 3 to 6, including all stereoisomers and mixtures thereof, and etherified or esterified free hydroxyl groups in R ^ ³ and R ^"14 , free

Carbonyl groups in A and R ^{13 are} ketalized, converted into an enol ether or reduced, and free acid groups in A in whose salts can be converted with bases.

B stands for a C7-C12 fragment (epothilone counting) of the general formula

B wherein R ^3a 'and R5' have the meanings already given for R ^a and R ⁵ , and V is an oxygen atom, two alkoxy groups OR ^{1 7} , a C2-C ^< | rj-alkylene-α, ω-dioxy group, which can be straight-chain or branched or H / OR ¹⁶ , W one oxygen atom, two alkoxy groups OR ^{1 9} , one C2-C- | o-alkylene-α, ω-dioxy group, which can be straight-chain or branched or

H / OR18, R16 _; R18 independently of one another are hydrogen or a protective group PG ^ R17, R ^ ⁹ independently of one another are C 1 -C 20 -alkyl.

C stands for a C13-C16 fragment (epothilone counting) of the general formula

worin R³' die bereits in der allgemeinen Formel I für R³ genannte Bedeutung hat und R⁷' ein Wasserstoffatom,

wherein R ³ 'has the meaning already given for R ³ in the general formula I and R ⁷ ' is a hydrogen atom,

R ² 0 is a hydrogen atom or a protective group PG ² R ^{2 "1 is} a hydroxyl group, halogen, a protected hydroxyl group

OPG ³ , a phosphonium halide residue PPh3 ⁺ Hal ^" (Ph = phenyl; Hai = F, Cl, Br, I), a phosphonate residue P (0) (OQ) 2 (Q = C- | -C ^« ι o-alkyl or phenyl ) or a phosphine oxide residue P (O) Ph2 (Ph = phenyl), U one oxygen atom, two alkoxy groups OR ²³ , one C2-C- | fj-alkylene, ω-dioxy group, which can be straight-chain or branched, H / OR ⁹ or a grouping CR ^ ORI 1, where

R ^{23 represents} a C 1 -C 20 -alkyl radical,

R ⁹ for hydrogen or a protective group PG ³ , RI O, R ^" ! 1 are the same or different and for hydrogen, a C- | -C20-alkyl, aryl, C7-C20-aralkyl radical or R ^' O and R1 1 together with the methylene carbon atom together represent a 5- to 7-membered carbocyclic ring.

As alkyl groups Rl ^a , Rl b R2a, _R 2b _R 3a, _R 4, R5, _R 8 _{> R} 10 _> R1 1, _R 13b Rl4b_ Rl 5a_ _R 15b Rl7 _f R19 _and R ²³ are straight or branched chain alkyl groups with 1 -20 carbon atoms to consider, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl.

The alkyl groups Rl, Rl b R ^2a , R ² b, _R 3a _{f R} 4, R5_ R8 _TR 10 _f R1 1, Rl 3b_ Rl4b _> Rl 5a _ι Rl 5b_ R17_ R19 _unc j R23 can be perfluorinated or substituted by 1 -5 Halogen atoms, hydroxyl groups, Cι-C4 alkoxy groups, C6-C12 aryl groups (which can be substituted by 1 -3 halogen atoms). As aryl radical Rl ^a , Rl b R ^2a , R ² b, R3a _ _R 4 _{f R} 5 _{ι R} 8 _t RI O, R1 1, _R 13b _R 14b, R ^ 5a _{un (} j Rl 5b come 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, which can be mono- or polysubstituted by halogen, OH, O-alkyl, CO ₂ H, CO ₂ -alkyl, -NH ₂ , -NO ₂ , -N3, -CN, C- | -C20-alkyl, C-ι-C20-acyl, Cι-C20-acyloxy groups, in question. Heteroatoms in the heteroaryl residues can be oxidized; for example, the thiazole ring can be in the form of the N-oxide. The aralkyl groups in Rl ^a , R "^ _R 2a _{f R} 2b _{ι R} 3a _ _R 4_ _R 5 _{> R} 8 _{f R} 10 _{t R} 11 _ _R 13b R ^4b , Rl5a _{and R} 15b can contain up to 14 C atoms in the ring, preferably 6 to 10 and in the alkyl chain contain 1 to 8, preferably 1 to 4. Examples of suitable aralkyl radicals are benzyl, phenylethyl, naphthyimethyl, naphthylethyl, furylmethyl, thienylethyl, pyridylpropyl. The rings can be mono- or polysubstituted by halogen , OH, O-alkyl, CO2H, Cθ2-alkyl, -NO2, -N3, -CN, CiC ^ o-alkyl, Cι-C-20-acyl, C <| -C20 acyloxy groups.

The alkoxy groups contained in X in the general formula I should each contain 1 to 20 carbon atoms, with methoxy, ethoxy, propoxy, isopropoxy and t-butyloxy groups being preferred. Representatives of the protective groups PG are alkyl- and / or aryl-substituted silyl, C- | -C20-alkyl, C4-C7-cycloalkyl, which can additionally contain an oxygen atom in the ring, aryl, C7-C20-aralkyl, C < | -C2fj-Acyl and Aroyl to name.

The alkyl, silyl and acyl radicals for the protective groups PG are the radicals known to the person skilled in the art. Preferred are easily removable alkyl or silyl residues from the corresponding alkyl and silyl ethers, such as, for example, methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethyisilyl, tert-butyldimethylsilyl, tert.-butyldiphenyldiphenyldiphenyl -, Tribenzylsilyl, triisopropylsilyl, benzyl, para-nitrobenzyl, para-methoxybenzyl radical and alkylsulfonyl and arylsulfonyl radicals. As acyl residues e.g. Formyl, acetyl, propionyl, isopropionyl, pivalyl, butyryl or benzoyl, which can be substituted with amino and / or hydroxyl groups, into question.

The acyl groups PG ^X and PG ^Z in R ⁹ and R ¹² can contain 1 to 20 carbon atoms, formyl, acetyl, propionyl, isopropionyl and pivalyl groups being preferred.

The index m in the alkylene group formed from R ^{1 a} and Rl b is preferably 1, 2, 3 or 4.

The C2-C- | o-alkylene-α, ω-dioxy group which is possible for X is preferably an ethylene ketal or neopentyl ketal group.

Halogen means a fluorine, chlorine, bromine or iodine atom. The compounds mentioned below are preferred according to the invention:

(4S, 7R, 8R, 9E, 13Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5,7,9,13-pentamethyl-cyclohexadeca-9,13-diene-2,6-dione

(4S, 7R, 8R, 9E, 13E, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5,7,9,13-pentamethyl-cyclohexadeca-9,13-diene-2,6-dione

(1 S, 2E, 6E, 9S (E), 13S, 16R) -9- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -

2,6,14,14,16-pentamethyl-10,17-dioxabicyclo [11.3.1] heptadec-2,6-diene-11, 15-dione

(4S, 7R, 8Z, 10E, 13E, 16S (E)) - 4-hydroxy-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5, 7,9,13-pentamethyl-cyclohexadec-8,10,13-triene-2,6-dione

(4S, 7R, 8E, 10E, 13E, 16S (E)) - 4-hydroxy-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5, 7,9,13-pentamethyl-cyclohexadec-8, 10,13-triene-2,6-dione

(1 S, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -8, 8,10,12,16-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione

(1 R, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -8, 8,10,12,16-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadec-

12-en-5,9-dione

(1 S, 3S (E), 7S, 10R, 11 R, 12E, 16S) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -8, 8,10,12,16-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadec-

12-en-5,9-dione (1S, 3S (E), 7S, 10R, 11 R, 12RS, 14RS, 17R) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -8 , 8,10,12,17-pentamethyl-4,13,18- trioxatricyclo [15.1.0.0 ^12-14] octadecane-5,9-dione

(1 RS, 2R, 3R, 6S, 10S (E), 12Z, 16RS) -2,6-dihydroxy-10- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1, 3rd , 5,5,13-pentamethyl-9,17-dioxabicyclo [14.1.0] heptadec-12-en-4,8-dione

(4S, 7R, 8R, 9E, 13Z, 16S (E)) - 4,8-Dihydroxy-7-ethyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1- oxa-5,5,9,13-tetramethyl-cyclohexadeca-9,13-diene-2,6-dione

(4S, 7R, 8R, 9E, 13E, 16S (E)) - 4,8-dihydroxy-7-ethyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1- oxa-5,5,9,13-tetramethyl-cyclohexadeca-9,13-diene-2,6-dione

(1S, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-10-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione

(1 R, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-10-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl ) -8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione

(1 S, 3S (E), 7S, 10R, 11 R, 12E, 16S) -7, 11 -dihydroxy-10-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl ) -8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione

(1S, 3S (E), 7S, 10R, 11 R, 12RS, 14RS, 17R) -7,11-dihydroxy-10-ethyl-3- (1-methyl-

2- (2-methyl-4-thiazolyl) ethenyl) -8,8,12,17-tetramethyl-4,13,18- trioxatricyclo [15.1.0.0 ^12-14] octadecane-5,9-dione

(1 RS, 2R, 3R, 6S, 10S (E), 12Z, 16RS) -2,6-dihydroxy-3-ethyl-10- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1,5,5,13-tetramethyl-9,17-dioxabicyclo [14.1.0] heptadec-12-en-4,8-dione

(4S, 7R, 8R, 9E, 13Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-oxa-5,5,7, 9,13-pentamethyl-cyclohexadeca-9,13-diene-2,6-dione (4S, 7R, 8R, 9E, 13E, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-oxa-5,5,7, 9,13-pentamethyl-cyclohexadeca-9,13-diene-2,6-dione

(1S, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-pyridyl) ethenyl) -8,8,10,12 , 16-pentamethyl-4,17-dioxabicycio [14.1.0] heptadec-12-en-5,9-dione

(1 R, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-pyridyl) ethenyl) -8,8,10, 12,16-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione

(1S, 3S (E), 7S, 10R, 11R, 12E, 16S) -7,11-dihydroxy-3- (1-methyl-2- (2-pyridyl) - 8,8,10,12,16- pentamethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione

(1S, 3S (E), 7S, 10R, 11 R, 12RS, 14RS, 17R) -7,11-dihydroxy-3- (1-methyl-2- (2-pyridyl) ethenyl) -8.8, 10 , 12, 17-pentamethyl-4,13, 18- trioxatricyclo [15.1.0.0 ^12-14] octadecane-5,9-dione

(1 RS, 2R, 3R, 6S, 10S (E), 12Z, 16RS) -2,6-dihydroxy-10- (1-methyl-2- (2-pyridyl) ethenyl) -1, 3.5.5 , 13-pentamethyl-9,17-dioxabicyclo [14.1.0] heptadec-12-en-4,8-dione

(4S, 7R, 8R, 9E, 13Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5- (1,3-trimethylene) -7,9,13-trimethyl-cyclohexadeca- 9,13-diene-2,6-dione

(4S, 7R, 8R, 9E, 13E, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5- (1,3-trimethylene) -7,9,13-trimethyl-cyclohexadeca-

9,13-diene-2,6-dione

(1 S, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -8, 8- (1,3-trimethylene) -10,12,16-trimethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione

(1 R, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -8, 8- (1,3-trimethylene) -10,12,16-trimethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione (1S, 3S (E), 7S, 10R, 11 R, 12E, 16S) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -8.8 - (1, 3-trimethylene) -10,12,16-trimethyl-4, 17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione

(1 S, 3S (E), 7S, 10R, 11 R, 12RS, 14RS, 17R) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 8,8- (1, 3-trimethylene) -10,12,17-trimethyl-4,13,18- trioxatricyclo [15.1.0.0 ^12-14] octadecane-5,9-dione

(1 RS, 2R, 3R, 6S, 10S (E), 12Z, 16RS) -2,6-dihydroxy-10- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -5.5 -trimethylene-1, 3, 13-trimethyl-9, 17-dioxabicyclo [14.1.0] heptadec-12-en-4,8-dione

(4S, 7R, 8R, 9E, 13Z, 16S (E)) - 4,8-dihydroxy-7-ethyl-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-oxa-5, 5,9,13-tetramethyl-cyclohexadeca-9,13-diene-2,6-dione

(4S, 7R, 8R, 9E, 13E, 16S (E)) - 4,8-dihydroxy-7-ethyl-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-oxa-5, 5,9,13-tetramethyl-cyclohexadeca-9,13-diene-2,6-dione

(1 S, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7, 11 -dihydroxy-10-ethyl-3- (1-methyl-2- (2-pyridyl) ethenyl) -8, 8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-ene-5,9-dione

(1 R, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-10-ethyl-3- (1-methyl-2- (2-pyridyl) ethenyl) -8, 8, 12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-ene-5,9-dione

(1 S, 3S (E), 7S, 10R, 11 R, 12E, 16S) -7,11-dihydroxy-10-ethyl-3- (1-methyl-2- (2-pyridyl) -8.8, 12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione

(1S, 3S (E), 7S, 10R, 11 R, 12RS, 14RS, 17R) -7,11-dihydroxy-10-ethyl-3- (1-methyl-2- (2-pyridyl) -8, 8 , 12, 17-tetramethyl-4, 13,18- trioxatricyclo [15.1.0.0 ^12-14] octadecane-5,9-dione

(1 RS, 2R, 3R, 6S, 10S (E), 12Z, 16RS) -2,6-dihydroxy-3-ethyl-10- (1-methyl-2- (2-pyridyl) ethenyl) -1.5 , 5,13-tetramethyl-9,17-dioxabicyclo [14.1.0] heptadec-12-ene-4,8-dione (4S, 7R, 8R, 9E, 13Z, 16S (E)) - 4,8-Dihydroxy-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-oxa-5,5- (1st , 3-trimethylene) -7,9,13-trimethyl-cyclohexadeca-9,13-diene-2,6-dione

(4S, 7R, 8R, 9E, 13E, 16S (E)) - 4,8-Dihydroxy-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-oxa-5,5- (1st , 3-trimethylene) -7,9,13-trimethyl-cyclohexadeca-9,13-diene-2,6-dione

(1 S, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-pyridyl) ethenyl) -8.8- (1st , 3-trimethylene) -10,12,16-trimethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione

(1 R, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-pyridyl) ethenyl) -8.8- (1st , 3-trimethylene) -10,12,16-trimethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione

(1 S, 3S (E), 7S, 10R, 11 R, 12E, 16S) -7,11-dihydroxy-3- (1-methyl-2- (2-pyridyl) ethenyl) -8.8- (1st , 3-trimethylene) -10,12,16-trimethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione

(1S, 3S (E), 7S, 10R, 11 R, 12RS, 14RS, 17R) -7,11-dihydroxy-3- (1-methyl-2- (2-pyridyl) ethenyl) -8.8- ( 1, 3-trimethylene) -10,12,17-trimethyl-4,13,18- trioxatricyclo [15.1.0.0 ^12-14] octadecane-5,9-dione

(1 RS, 2R, 3R, 6S, 10S (E), 12Z, 16RS) -2,6-dihydroxy-10- (1-methyl-2- (2-pyridyl) ethenyl) -5,5-trimethylene-1 , 3,13-trimethyl-9,17-dioxabicyclo [14.1.0] heptadec-12-en-4,8-dione

(4S, 7R, 8R, 9E, 13Z, 16S (E)) - 4,8-dihydroxy-16- (2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5,5,7, 9,13-pentamethyl-cyclohexadeca-9,13-diene-2,6-dione

(4S, 7R, 8R, 9E, 13E, 16S (E)) - 4,8-dihydroxy-16- (2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5,5,7, 9,13-pentamethyl-cyclohexadeca-9,13-diene-2,6-dione

(1 S, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-3- (2- (2-methyl-4-thiazolyl) ethenyl) -8.8, 10, 12, 16-pentamethyl-4, 17-dioxabicyclo [14.1.Ojheptadec-12-en-5,9-dione (1 R, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-3- (2- (2-methyl-4-thiazolyl) ethenyl) -8,8,10, 12,16-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadec-

12-en-5,9-dione

(1 S, 3S (E), 7S, 10R, 11 R, 12E, 16S) -7,11-dihydroxy-3- (2- (2-methyl-4-thiazolyl) ethenyl) -8,8,10, 12,16-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione

(1 S, 3S (E), 7S, 10R, 11 R, 12RS, 14RS, 17R) -7,11-dihydroxy-3- (2- (2-methyl-4-thiazolyl) ethenyl) -8.8, 10,12,17-pentamethyl-4,13,18- trioxatricyclo [15.1.0.0 ^12-14] octadecane-5,9-dione

(1 RS, 2R, 3R, 6S, 10S (E), 12Z, 16RS) -2,6-dihydroxy-10- (2- (2-methyl-4-thiazolyl) ethenyl) -1, 3.5.5 , 13-pentamethyl-9,17-dioxabicyclo [14.1.0] heptadec-12-en-4,8-dione

(4S, 7R, 8R, 9E, 13Z, 16S (E)) - 4,8-dihydroxy-16- (2- (2-pyridyl) ethenyl) -1-oxa- 5,5,7,9, 13- pentamethyl-cyclohexadeca-9,13-diene-2,6-dione

(4S, 7R, 8R, 9E, 13E, 16S (E)) - 4,8-dihydroxy-16- (2- (2-pyridyl) ethenyl) -1-oxa- 5,5,7,9, 13- pentamethyl-cyclohexadeca-9,13-diene-2,6-dione

(1 S, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-3- (2- (2-pyridyl) ethenyl) - 8,8,10,12,16- pentamethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione

(1 R, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-3- (2- (2-pyridyl) ethenyl) - 8,8,10,12,16- pentamethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione

(1S, 3S (E), 7S, 10R, 11 R, 12E, 16S) -7,11-dihydroxy-3- (2- (2-pyridyl) ethenyl) - 8,8,10,12,16-pentamethyl -4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione

(1S, 3S (E), 7S, 10R, 11 R, 12RS, 14RS, 17R) -7,11-dihydroxy-3- (2- (2-pyridyl) ethenyl) -8,8,10,12,17 pentamethyl-4,13,18- trioxatricyclo [15.1.0.0 ^12-14] octadecane-5,9-dione

(1 RS, 2R, 3R, 6S, 10S (E), 12Z, 16RS) -2,6-dihydroxy-10- (2- (2-pyridyl) ethenyl) -1,3,5,5,13-pentamethyl -9.17-dioxabicyclo [14.1.0] heptadec-12-ene-4,8-dione (4S, 7R, 8R, 9E, 13Z, 16S (E)) - 4,8-dihydroxy-7-ethyl-16- (2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5,9,13-tetramethyl-cyclohexadeca-9,13-diene-2,6-dione

(4S, 7R, 8R, 9E, 13E, 16S (E)) - 4,8-dihydroxy-7-ethyl-16- (2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5,9,13-tetramethyl-cyclohexadeca-9,13-diene-2,6-dione

(1 S, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-10-ethyl-3- (2- (2-methyl-4-thiazolyl) ethenyl) -8, 8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione

(1 R, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-10-ethyl-3- (2- (2-methyl-4-thiazolyl) ethenyl) -8, 8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione

(1 S, 3S (E), 7S, 10R, 11 R, 12E, 16S) -7,11-dihydroxy-10-ethyl-3- (2- (2-methyl-4-thiazolyl) ethenyl) -8, 8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione

(1 S, 3S (E), 7S, 10R, 11 R, 12RS, 14RS, 17R) -7,11-dihydroxy-10-ethyl-3- (2- (2-methyl-4-thiazolyl) ethenyl) - 8,8,12,17-tetramethyl-4,13,18-trioxatricyclo [15.1.0.0 ^12'14 ] octadecane-5,9-dione

(1 RS, 2R, 3R, 6S, 10S (E), 12Z, 16RS) -2,6-dihydroxy-3-ethyl-10- (2- (2-methyl-4-thiazolyl) ethenyl) -1, 5 , 5,13-tetramethyl-9,17-dioxabicyclo [14.1.0] heptadec-12-ene-4,8-dione

Representation of partial fragments A:

The partial fragments (synthesis building blocks) of the general formula A can be prepared as described in DE 197 51 200.3 or the corresponding PCT / EP98 / 05064.

The partial fragments B are represented according to scheme 1:

Scheme 1

B-B-Ill B-IV

OPG ° OPG ^* ? PG "

"OPG ⁰ ..OH

B-V B-Vl B-Vll

B-Vl II B-IX B-X

B-Xl B-Xll

OPG "OH

B-IX, G ^ JDPG ¹ '

^ "E ' _R = ^ \ ^ - _E -" G _^ _, OPG'

B-Xl II B-XIV

n V

, G ^ .OPG "

B-XV Step a (B-Il => B-III):

A hydroxyl group in B-II is protected by the methods known to the person skilled in the art. The protective groups PG ³ include the protective groups known to the person skilled in the art, such as, for example, methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert.-butyldimethylsilyl, tert.-butyldiphenylsilylsilyl, tribenzylsilyl, tribenzylsilylsilyl, tribenzylsilylsilyl, tribenzylsilylsilyl and tribenzylsilylsilylsoles -, Benzyl, para-nitrobenzyl, para-methoxybenzyl, formyl, acetyl, 1, 1, 1-trichloroacetyl, propionyl, isopropionyl, pivalyl, butyryl or benzoyl in question. An overview can be found, for example, in "Protective Groups in Organic Synthesis" (Theodora W. Green, John Wiley and Sons).

Preferred radicals are those which can be cleaved reductively or under basic reaction conditions, such as the acetyl, 1, 1, 1 trichloroacetyl, propionyl, isopropionyl, pivalyl, butyryl or benzoyl radical. The acetyl radical is particularly preferred.

Step b (B-Ill => B-IV):

The reduction of the carbonyl group in B-III can be carried out by the methods known to the person skilled in the art. As reducing agents are e.g. Sodium borohydride, diisobutyl aluminum hydride and complex metal hydrides such as Lithium aluminum hydride in question.

Step c (B-IV => B-V):

The free hydroxy group in B-IV is protected by the methods known to the person skilled in the art. The protective groups PG ⁹ are the protective groups known to the person skilled in the art, as already described above for PG ^ in step a (B-II

=> B-Ill) were called into question.

Protective groups which can be cleaved under the action of fluoride, such as e.g. the trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl radical.

The tert-butyldimethylsilyl, the triisopropylsilyl and the tert.-butyldiphenylsilyl radical are particularly preferred.

Step d (BV => B-VI): The protective group PG ^ introduced in step a (B-Il => B-III) is removed by the methods known to the person skilled in the art. If it is an ester, it is either removed reductively, for example with diisobutylaluminium hydride, lithium aluminum hydride etc., or basicly. Suitable for saponification are carbonates in alcoholic solution such as potassium carbonate in methanol, aqueous solutions of alkali hydroxides such as lithium hydroxide or sodium hydroxide using organic, water-miscible solvents such as methanol, ethanol, tetrahydrofuran or dioxane.

Step e (B-Vl => B-Vl I):

The oxidation of the primary alcohol in B-VI to the aldehyde takes place according to the methods known to the person skilled in the art. Examples include oxidation with manganese dioxide, pyridinium chlorochromate, pyridinium dichromate, chromium trioxide-pyridine complex, oxidation according to Swern or related methods, e.g. using oxalyl chloride in dimethyl sulfoxide, using Dess-Martin periodinane, using nitrogen oxides such as e.g. N-methyl-morpholino-N-oxide in the presence of suitable catalysts such as e.g. Tetrapropylammonium perruthenate in inert solvents. Oxidation according to Swern and with N-methyl-morpholino-N-oxide using tetrapropylammonium perruthenate is preferred.

Step f (B-Vll => B-Vlll):

The compound B-VIII is made according to the methods known to those skilled in the art, e.g. implemented in a Wittig or Wittig / Horner reaction or an analog variant. The Wittig and Wittig / Horner reaction is preferred using phosphonium halides of the type

R ^a OC (= W) CHR 'P (Ph) ₃ ⁺ Hal-, R ^3a ' θC (= W) CHR ^, P (alkyl) ₃ ⁺ Ha | - or phosphonates of the type R ^3a OC (= W) CHR ⁴ 'P (O) (OAIkyl) ₂ , R3 ^a OC (= W) CHR ⁴ ' P (O) (OAryl) ₂ with Ph equal to phenyl, W = oxygen, R ^3a ', R ⁴ ' aryl and halogen in the already meanings mentioned with strong bases such as, for example, n-butyllithium, potassium tert.-butanolate, sodium ethanolate,

Sodium hexamethyldisilazane; n-butyllithium is preferred as the base.

Step g (B-VIII => B-IX):

The ester B-VIII is reduced to the alcohol B-IX by the methods known to the person skilled in the art. Aluminum hydrides such as e.g. Diisobutyl aluminum hydride or lithium aluminum hydride. The reaction takes place in an inert solvent such as e.g. Toluene.

Step h (B-IX =.> B-X):

The oxidation of alcohol B-IX to ketone (W in the meaning of

Oxygen) of the general formula BX is carried out according to those mentioned under e) Method. Oxidation with manganese dioxide is preferred. The carbonyl group can optionally be converted into a ketal by the processes known to the person skilled in the art (W in the meaning of two alkoxy groups OR ^ ⁹ or a C2 ~ Cl θ "alkylene-α, ω-dioxy group).

Step i (B-X = B-Xl):

The optional conversion of the aldehydes BX to alcohols of the general formula B-Xl takes place according to the methods known to the person skilled in the art with organometallic compounds of the general formula MR ^3a ', in which M is an alkali metal, preferably lithium or a divalent metal MX, in which X is a halogen represents and the radical R ^3a 'has the meaning given above. Magnesium and zinc are preferred as divalent metal, and chlorine, bromine and iodine are preferred as halogen X.

Step k (B-Xl => B-Xll):

The oxidation of the alcohol B-Xl to the ketone of the general formula B-Xll (W in the meaning of oxygen) takes place according to the process mentioned under e). Oxidation with N-methylmorpholino-N-oxide using tetrapropylammonium perruthenate is preferred. The carbonyl group can optionally be converted into a ketal by the processes known to the person skilled in the art (W in the meaning of two alkoxy groups OR ^ ⁹ or a C2-C- | rj-alkylene-α, ω-dioxy group).

Step I (B-IX => B-Xl II): The hydroxyl group in B-IX can be provided with a protective group PG ^' O by the processes mentioned under a). Preference is given to silicon-containing protective groups which can be cleaved under acidic reaction conditions or using fluoride, such as, for example, the tetrahydropyranyl, trimethylsilyl, triethylsilyl, tert.-butyldimethylsilyl, tert.-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl radical.

Step m (B-Xl II => B-XIV):

The protection group PG ⁹ introduced under step c) is according to the

Process known to those skilled in the art.

Step n (B-XV => B-XVI):

The oxidation of the alcohol B-XV to a compound of the general formula

B-XVI (V in the meaning of oxygen) takes place according to those mentioned under e) Method. Preferred is the use of the chromium trioxide-pyridine complex or the oxidation with N-methyl-morpholino-N-oxide using tetrapropylammonium perruthenate.

The carbonyl group can optionally be converted into a ketal by the processes known to the person skilled in the art (V in the meaning of two alkoxy groups OR ¹⁹ or one C2-C- _| o-alkylene-α, ω-dioxy group).

Representation of the partial fragments C:

The partial fragments (synthesis building blocks) of the general formula C can be prepared as described in DE 197 51 200.3 or in the corresponding PCT / EP98 / 05064.

Representation of the partial fragments ABC and their cyclization

Partial fragments of the general formula AB

FROM,

_R3a_{ι R}5_{> R}13_ _R14_f Q, E, V und Z die bereits genannten Bedeutungen haben und PG^"14 ein Wasserstoffatom oder eine Schutzgruppe PG darstellt, werden aus den zuvor beschriebenen Fragmenten A und B nach dem in Schema 2 gezeigten Verfahren erhalten.where Rl ^a ', Rlb',

_R 3a _{ι R} 5 _{> R} 13_ _R 14 _f Q, E, V and Z have the meanings already mentioned and PG ^{"14 represents} a hydrogen atom or a protective group PG, are made from the fragments A and B described above according to that shown in Scheme 2 Procedure received.

Scheme 2

FROM

Step a (A + B => AB):

The compound B, in which W has the meaning of an oxygen atom and any additional carbonyl groups present are protected, is alkylated with the enolate of a carbonyl compound of the general formula A. The enolate is formed by the action of strong bases such as e.g. Lithium diisopropylamide, lithium hexamethyldisilazane produced at low temperatures. Partial fragments of the general formula ABC

ABC,

_R3a_{j R}5_{) R}6_ _R7_ R8_{J R}13_{) R}14_? Q, E, U und Z die bereits genannten Bedeutungen haben, werden aus den zuvor beschriebenen Fragmenten AB und C nach dem in Schema 3 gezeigten Verfahren erhalten.where Rl ^a ', Rl b', R2a ' ₎

_R 3a _{j R} 5 _{) R} 6_ _R 7_ R8 _JR 13 _{) R} 14 _? Q, E, U and Z have the meanings already mentioned, are obtained from the fragments AB and C described above by the method shown in Scheme 3.

Scheme 3

Schritt b (AB + C = ABC):

Step b (AB + C = ABC):

The compound C, in which R2 has the meaning of a Wittig salt and any additional carbonyl groups which may be present are protected, is deprotonated by a suitable base, such as, for example, n-butyllithium, lithium diisopropylamide, potassium, tert.-butanolate, sodium or lithium hexamethyldisiiazide, and with a compound AB, in which V has the meaning of an oxygen atom, implemented. Step c (ABC => I): The compounds ABC, in which R ^{13 is} a carboxylic acid CO2H and R20 is a hydrogen atom, are added to the compounds of the formula I, in which Y is the Meaning of an oxygen atom, um. The method described in "Reagents for Organic Synthesis, Vol. 16, p 353" is preferred using 2,4,6-trichlorobenzoic acid chloride and suitable bases such as, for example, triethylamine, 4-dimethylaminopyridine, sodium hydride.

Step d (ABC = I):

The compounds ABC, in which R ^{13 represents} a group CH2OH and R20 represents a hydrogen atom, can preferably be used using

Triphenylphosphine and azodiesters such as

Azodicarboxylic acid diethyl ester to compounds of the formula I in which Y is the

Has the meaning of two hydrogen atoms.

The compounds ABC, in which R1 ^{3 represents} a group CH2θSθ2Al yl or CH2OSO2A1NI or CH2θSθ2Aral yl and R 0 represents a hydrogen atom, can be deprotonated with suitable bases, for example

Sodium hydride, n-butyllithium, 4-dimethylaminopyridine, Hünig base,

Alkylihexamethyldisilazanes to compounds of formula I in which Y is the

Has the meaning of two hydrogen atoms, cyclize. The flexible functionalization of the described modules A, B and C also ensures a linking sequence which deviates from the method described above and which leads to the modules ABC. These procedures are summarized in the following table:

Using these methods, building blocks A, B and C can be linked as shown in Scheme 4:

Scheme 4

b or e c or d

ABC

A + B A-B + C

c or d C-B-A b or <

b or e

C-A-B c or d A + C ► C-A + B

ι or e B-C-A

: or d A-C-B

Free hydroxyl groups in I, A, B, C, AB, ABC can be further functionally modified by etherification or esterification, free carbonyl groups by ketalization, enol ether formation or reduction. The compounds of the formulas B, AB, CB, ABC and I in which GE has a double bond can be converted into further compounds of the formulas B, AB, CB by hydrogenation, deuteration, tritiation, epoxidation, bis-hydroxylation, hydroboration. ABC and I can be transferred according to methods familiar to those skilled in the art for these reaction steps. If R3b is a hydroxy group, this can be eliminated to the diene.

The invention relates to all stereoisomers of these compounds and also their mixtures. Biological effects and areas of application of the new derivatives:

The new compounds of formula I are valuable pharmaceuticals. They interact with tubulin by stabilizing formed microtubules and are therefore able to influence cell division in a phase-specific manner. This concerns above all fast growing, neoplastic cells, the growth of which is largely unaffected by intercellular control mechanisms. In principle, active substances of this type are suitable for the treatment of malignant tumors. Areas of application include the therapy of ovarian, stomach, colon, adeno, breast, lung, head and neck carcinomas, malignant melanoma, acute lymphocytic and myelocytic leukemia. Because of their properties, the compounds according to the invention are suitable in principle for anti-angiogenesis therapy and for the treatment of chronic inflammatory diseases such as, for example, psoriasis or arthritis. In order to avoid uncontrolled cell growth on and the better compatibility of medical implants, they can in principle be applied or incorporated into the polymeric materials used for this. The compounds according to the invention can be used alone or to achieve additive or synergistic effects in combination with other principles and classes of substances which can be used in tumor therapy. Examples include the combination with

Platinum complexes such as Cisplatin, carboplatin,

Intercalating substances e.g. from the class of anthracyclines such as Doxorubicin or from the class of antrapyrazoles such as e.g. CI-941,

Substances interacting with tubulin e.g. from the class of Vinka alkaloids such as Vincristine, vinblastine or from the taxane class such as Taxol, Taxotere or from the macrolide class such as e.g. Rhizoxin or other compounds such as e.g. Colchicine, combretastatin A-4, • DNA topoisomerase inhibitors such as e.g. Camptothecin, etoposide, topotecan, teniposide,

Folate or pyrimidine antimetabolites such as Lometrexol, gemcitubin,

DNA alkylating compounds such as e.g. Adozelesin, dystamycin A,

Inhibitors of growth factors (e.g. PDGF, EGF, TGFb, EGF) such as e.g. Somatostatin, suramin, bombesin antagonists,

Inhibitors of protein tyrosine kinase or protein kinases A or C such as, for example, erbstatin, genistein, staurosporin, llmofosin, 8-CI-cAMP, Anti-hormones from the class of antigestagens such as mifepristone, onapristone or from the class of anti-estrogens such as tamoxifen or from the class of anti-androgens such as cyproterone acetate,

Metastasis inhibiting compounds e.g. from the class of eicosanoids such as PGI2, PGE- | , 6-oxo-PGE- | as well as their more stable

Derivatives (e.g. Iloprost, Cicaprost, Misoprostol).

Inhibitors of oncogenic RAS proteins which influence mitotic signal transduction, for example inhibitors of famesyl protein transferase, natural or artificially produced antibodies which are directed against factors or their receptors which promote tumor growth, for example the erbB2 antibody ,

The invention also relates to pharmaceuticals based on the pharmaceutically acceptable, i.e. in the doses used, non-toxic compounds of the general formula I, if appropriate together with the customary auxiliaries and carriers.

The compounds according to the invention can be processed into pharmaceutical preparations for enteral, percutaneous, parenteral or local application according to known galenical methods. They can be administered in the form of tablets, dragées, gel capsules, granules, suppositories, implants, injectable sterile aqueous or oily solutions, suspensions or emulsions, ointments, creams and gels. The active ingredient (s) can be combined with the auxiliaries commonly used in galenics, e.g. Gum arabic, talc, starch, mannitol, methyl cellulose, lactose, surfactants such as tweens or myrj, magnesium stearate, aqueous or non-aqueous vehicles, paraffin derivatives, wetting, dispersing, emulsifying, preserving agents and flavoring agents for flavor correction (e.g. essential oils). The invention thus also relates to pharmaceutical compositions which contain at least one compound according to the invention as active ingredient. One dose unit contains about 0.1-100 mg of active ingredient (s). The dosage of the compounds according to the invention in humans is about 0.1-1000 mg per day.

Those compounds of the formulas B, AB, CB, ABC and in particular I which have one or two double bonds in section G'-GEE 'are used also represent the valuable starting products for the production of the corresponding radio-labeled compounds.

The following examples serve to explain the invention in more detail without wishing to restrict it:

example 1

(4S, 7R, 8R, 9 (E), 13 (Z), 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 1-oxa-5,5,7,9,13-pentamethyl-cyclohexadeca-9,13-diene-

2.6-dion

Example 1a

(4RS) -1-acetoxy-pentan-4-one

The solution of 18.5 g (181 mmol) of 4-oxopetan-1-ol in 70 ml of anhydrous dichloromethane is mixed with 20 ml of pyridine, a spatula tip of 4-dimethylaminopyridine, 23 ml of acetic anhydride under a dry atmosphere of argon and stirred 15 Hours at 23 ° C. It is poured into a saturated sodium bicarbonate solution, extracted several times with dichloromethane and the combined organic extracts are dried over sodium sulfate. After filtration and removal of solvent, 24 g (166 mmol, 92%) of the title compound are isolated, which are reacted further without purification.

Example 1 b

(4RS) -1-acetoxy-pentan-4-ol

The solution of 23.5 g (163 mmol) of the compound shown in Example 1a is dissolved in a mixture of 11 tetrahydrofuran and 200 ml of methanol, cooled to 0 ° C. under an atmosphere of dry argon and mixed with 3.0 g Sodium borohydride. After 1 hour, a saturated ammonium chloride solution, diluted with water, extracted several times with ethyl acetate and the combined organic extracts dried over sodium sulfate. The residue obtained after filtration and removal of solvent is purified by chromatography on about 200 ml of fine silica gel using a gradient system composed of n-hexane and ethyl acetate. 20.4 g (140 mmol, 86%) of the title compound are isolated as a colorless oil.

1 H-NMR (CDCI ₃ ): δ = 1, 21 (3H), 1, 43-1, 87 (4H), 2.06 (3H), 3.83 (1 H), 4.09 (2H) ppm.

Example 1c (4RS) -1-Acetoxy-4 - [[(1, 1-dimethylethyl) diphenylsilyl] oxy] pentane

The solution of 20.4 g (140 mmol) of the compound shown in Example 1b in 480 ml of anhydrous dimethylformamide is mixed with 14.5 g of imidazole, 51.5 ml of tert-butyldiphenylchlorosilane under an atmosphere of dry argon and stirred for 16 hours at 23 ° C. It is poured into water, extracted several times with ethyl acetate, the combined organic extracts are washed with water and dried over sodium sulfate. After filtration and removal of the solvent, the residue is chromatographed on fine silica gel using a gradient system composed of n-hexane and ethyl acetate. 53 g (138 mmol, 98%) of the title compound are isolated as a colorless oil.

¹ H-NMR (CDCI ₃ ): δ = 1.05 (9H), 1.08 (3H), 1.41-1, 73 (4H), 2.02 (3H), 3.88 (1 H) , 3.98 (2H), 7.32-7.48 (6H), 7.69 (4H) ppm.

Example 1d (4RS) -4 - [[(1, 1-dimethylethyl) diphenylsilyl] oxy] pentan-1-ol

240 ml of a 1.2 M solution of diisobutylaluminum hydride in toluene are added to a solution of 53 g (138 mmol) of the compound shown in Example 1c in 320 ml of toluene at -60 ° C. under argon and the mixture is stirred for 2 hours at this temperature. 80 ml of isopropanol are then carefully added, and 125 ml of water are added after 10 minutes, the mixture is brought to 22 ° C. and the mixture is stirred at this temperature for 2 hours. The precipitate is filtered off, washed well with ethyl acetate and the filtrate is concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel using a gradient system composed of n-hexane and ethyl acetate. 38.2 g (112 mmol, 79%) of the title compound are isolated as a colorless oil. H-NMR (CDCI ₃ ): δ = 1.06 (9H), 1.09 (3H), 1.44-1, 67 (4H), 3.56 (2H), 3.92 (1H), 7.34-7.49 (6H), 7.69 (4H) ppm.

Example 1e (4RS) -4 - [[(1, 1-dimethylethyl) diphenylsilylJoxy] pentanal

To 14.6 ml of oxalyl chloride dissolved in 300 ml of dichloromethane, 24 ml of dimethyl sulfoxide dissolved in 50 ml of dichloromethane and are carefully added under argon at -70 ° C stir for 10 minutes at this temperature. A solution of 38.2 g (112 mmol) of the compound shown in Example 1d in 200 ml of methylene chloride is then added dropwise, and the mixture is stirred between -60 ° C. and -70 ° C. for 1 hour. Then 75 ml of triethylamine are added, the mixture is allowed to warm to 23 ° C., water is added and the mixture is extracted several times with dichloromethane. The combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. The residue obtained after filtration and removal of solvent is purified by chromatography on about 100 ml of fine silica gel using a gradient system composed of n-hexane and ethyl acetate. 41.7 g (max. 112 mmol) of the title compound are isolated as a colorless oil.

Example 1f

(6RS, 2E) -6 - [[(1,1-Dimethylethyl) diphenylsilyl] oxy] -2-methyl-hept-2-enoic acid ethyl ester Under a dry atmosphere of argon, the suspension of 8.9 g is added at 0 ° C. Sodium hydride (60%) in 100 ml of anhydrous dimethoxyethane with the solution of 48.3 ml of 2-

Phosphonopropionic acid triethyl ester in 100 ml of dimethoxyethane and after 45 minutes with the solution of 41.7 g (max. 112 mmol) of the compound shown in Example 1e in 100 ml. The mixture is allowed to warm to 23 ° C. and react for a further 15 hours. A saturated ammonium chloride solution is added, the mixture is diluted with water and the mixture is extracted several times with ethyl acetate and the combined organic extracts are dried over sodium sulfate. The residue obtained after filtration and removal of solvent is purified by chromatography on about 200 ml of fine silica gel using a gradient system composed of n-hexane and ethyl acetate. 46.4 g (109 mmol, 78%) of the title compound are isolated as a colorless oil. H-NMR (CDCI ₃ ): δ = 1.06 (9H), 1.09 (3H), 1.29 (3H), 1.45-1, 68 (2H), 1.78 (3H), 2nd , 19 (2H), 3.89 (1H), 4.19 (2H), 6.67 (1H), 7.32-7.48 (6H), 7.69 (4H) ppm.

Example 1g

(6RS, 2E) -6 - [[(1, 1-dimethylethyl) diphenyisilyl] oxy] -2-methylhept-2-en-1-ol 46.4 g (109 mmol) of the compound shown in Example 1f are reacted analogously to Example 1d and, after working up and purification, 34.9 g (91 mmol, 84%) of the title compound are isolated as a colorless oil.

1 H-NMR (CDCI ₃ ): δ = 1.06 (9H), 1.09 (3H), 1.39-1, 59 (2H), 1.60 (3H), 2.02 (2H), 3.85 (1H), 3.93 (2H), 5.24 (1H), 7.31-7.48 (6H), 7.69 (4H) ppm.

Example 1h (6RS, 2E) -6 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -2-methyl-hept-2-enal

The solution of 10 g (26 mmol) of the compound shown in Example 1g in 370 ml of anhydrous dichloromethane is mixed with 48.6 g of brown stone at 23 ° C., stirred for 2 hours, filtered through Celite and concentrated. 10 g (max. 26 mmol) of the title compound are isolated, which are reacted further without purification.

Example 1i (4S (4R, 5R, 6E, 10RS)) - 4- (10 - [[(1,1-dimethylethyl) diphenylsilyl] oxy] -3-oxo-2,4,6-trimethyl-5-hydroxy- undec-6-en-2-yl) -2,2-dimethyl- [1,3] dioxane

The solution of 4 ml of diisopropylamine in 90 ml of anhydrous tetrahydrofuran is cooled to -30 ° C. under an atmosphere of dry argon, mixed with 11.9 ml of a 2.4 molar solution of n-butyllithium in n-hexane and stirred for a further 15 minutes . The solution of 5.1 g (23.8 mmol) of (4S) -4- (2-methyl-3-oxopent-2-yl) -2,2-dimethyl- [1 , 3] dioxane in 95 ml of tetrahydrofuran and allowed to react for 1 hour. Then a solution of 10 g (max. 26 mmol) of the compound shown in Example 1 h in 90 ml of tetrahydrofuran is added, and after 45 minutes it is poured into saturated ammonium chloride solution. It is diluted with water, extracted several times with ethyl acetate, the combined organic extracts are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. After column chromatography on silica gel using a gradient system of n-hexane and ethyl acetate, 11.16 g (18.8 mmol, 79%) of the title compound are obtained. H-NMR (CDCI ₃ ): δ = 0.88-0.98 (3H), 1, 01-1, 73 (31 H), 1, 90-2.13 (2H), 3.09-3, 22 (1H), 3.42 (1H), 3.80-4.20 (5H), 5.49 (1H), 7.29-7.48 (6H), 7.68 (4H) ppm. Example 1j

(4S (4R, 5R, 6E, 10RS)) - 4- (10 - [[(1, 1-dimethylethyl) diphenylsilyl] oxy] -2,4,6-trimethyl-5- (tetrahydropyran-2-yloxy) - undec-6-en-2-yl) -2,2-dimethyl- [1,3] dioxane

To 11.16 g (18.7 mmol) of the compound shown in Example 1 i in 250 ml of dichloromethane is added at 23 ° C. under argon 18 ml of dihydropyran followed by 1.2 g of p-toluenesulfonic acid monohydrate. After stirring for 48 hours at 23 ° C., saturated sodium bicarbonate solution is added, the organic phase is separated off and extracted several times with dichloromethane. The combined organic extracts are washed with semi-saturated sodium chloride solution and dried over sodium sulfate. After filtration, the mixture is concentrated in vacuo. 14.6 g (max. 18.7 mmol) of the title compound are isolated as a crude product which is reacted further without purification.

Example 1k

(4S (4R, 5R, 6E, 10RS)) - 4- (10-hydroxy-3-oxo-2,4,6-trimethyl-5-

(tetrahydropyran-2-yloxy) -undec-6-en-2-yl) -2,2-dimethyl- [1,3] dioxane

39 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran are added under argon to a solution of 14.6 g (max. 18.7 mmol) of the compound shown in Example 1j in 200 ml of tetrahydrofuran and the mixture is stirred at 23 ° C. for 15 hours. It is poured into saturated ammonium chloride solution, extracted several times with ethyl acetate and the combined organic extracts are dried over sodium sulfate. The residue obtained after filtration and removal of solvent is purified by chromatography on 1 l of fine silica gel using a gradient system composed of n-hexane and ethyl acetate. 5.89 g (13.4 mmol, 71%) of the title compound are isolated as a colorless oil.

Example 11 (4S (4R, 5R, 6E)) - 4- (3,10-Dioxo-2,4,6-trimethyl-5- (tetrahydropyran-2-yloxy) - undec-6-en-2-yl) -2,2-dimethyl- [1,3] dioxane

The solution of 5.89 g (13.4 mmol) of the compound shown in Example 1 k in 200 ml of anhydrous dichloromethane is added Molecular sieve (4A), 2.71 g of N-methylmorpholino-N-oxide, 236 mg of tetrapropylammonium perruthenate and stirred for 16 hours at 23 ° C under an atmosphere of dry argon. The mixture is concentrated and the crude product obtained is purified by chromatography on about 200 ml of fine silica gel using a gradient system composed of n-hexane and ethyl acetate. 5.31 g (12.1 mmol, 90%) of the title compound are isolated as a colorless oil.

¹ H-NMR (CDCI ₃ ): δ = 0.83 + 1, 00 (3H), 1, 02-1, 91 (22H), 2.12 (3H), 2.15 (1 H), 2, 30 (1H), 2.43 (2H), 3.18-3.55 (2H), 3.68-4.22 (5H), 4.49 + 4.60 (1H), 5.25 (1H) ppm.

Example 1m

(4S (4R, 5R, 6E, 10E / Z, 13S, 14E)) - 4- (13 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] - 15- (2-methyl-4-thiazolyl) - 3-oxo-5- (tetrahydropyran-2-yloxy) -2,4,6,10,14-pentamethyl-pentadeca-6,10,14-trien-2-yl) -2,2-dimethyl- [1, 3] dioxane The suspension of 15.34 g (18.6 mmol) (5E, 3S) - [3 - [[(1, 1-dimethylethyl) diphenylsilyI] -oxy] -4-methyl-5- (2-methyl -thiazol-4-yl) -pent-4-en-1-yl] -triphenylphosphonium iodide in 90 ml of anhydrous tetrahydrofuran are added at 23 ° C under an atmosphere of dry argon with 18.6 ml of a 1 M solution of sodium bis - (Trimethylsilyl) amide in tetrahydrofuran and allowed to stir for 1.5 hours. The solution of 2.72 g (6.20 mmol) of the compound shown in Example 11 in 46 ml of tetrahydrofuran is slowly added dropwise to the red solution, the mixture is stirred for 2 hours, poured onto saturated ammonium chloride solution and extracted several times with ethyl acetate. The combined organic extracts are dried over sodium sulfate and concentrated in vacuo. After column chromatography on silica gel using a gradient system composed of n-hexane and ethyl acetate, in addition to 51% of the starting material, 1.92 g (2.24 mmol, 36%) of the title compound are obtained. ¹ H-NMR (CDCI ₃ ): δ = 0.82 + 0.99 (3H), 1.02-2.09 (39H), 1.95 (3H), 2.12-2.37 (2H) , 2.70 (3H), 3.18-3.54 (2H), 3.68-4.03 (4H), 4.07-4.22 (2H), 4.47 + 4.59 (1st H), 4.96 (1 H), 5.24 (1 H), 6.21 (1 H), 6.77 (1 H), 7.21-7.45 (6H), 7.57- 7.72 (4H) ppm. Example 1 n

(4S (4R, 5R, 6E, 10E / Z, 13S, 14E)) - 4- (13-Hydroxy-15- (2-methyl-4-thiazolyl) -3-oxo-5- (tetrahydropyran-2-yloxy ) -2,4,6,10,14-pentamethyl-pentadeca- 6,10,14-trien-2-yl) -2,2-dimethyl- [1,3] dioxane Analogously to Example 1 k, 3 is used , 0 g (3.5 mmol) of the compound shown in Example 1 m and, after working up and purification, isolated 2.0 g (3.24 mmol, 93%) of the title compound as a colorless oil.

¹ H-NMR (CDCI ₃ ): δ = 0.83 + 1.00 (3H), 1.02-1, 87 (25H), 1.91-2.50 (8H), 2.05 (3H) , 2.70 (3H), 3.19-3.56 (2H), 3.70-4.21 (6H), 4.52 + 4.61 (1H), 5.19 (1H), 5.29 (1H), 6.56 (1H), 6.94 (1H) ppm.

Example 1o

(3S, 6R, 7R, 8E, 12E / Z, 15S, 16E) -1, 3,15-tris - [[dimethyl (1, 1 - dimethylethyl) silyl] oxy] -17- (2-methyl-4- thiazolyl) -5-oxo-7- (tetrahydropyran- 2-yloxy) -4,4,6,8,12,16-hexamethyl-heptadeca-8,12,16-triene-1,3,5-triol

The solution of 2.3 g (3.72 mmol) of the compound shown in Example 1 n in a mixture of 120 ml of dichloromethane and 120 ml of anhydrous methanol is admixed with 1.3 g of rac at 0 ° C. under an atmosphere of dry argon .-Camphor-10-sulfonic acid and stirred for 1.5 hours. It is poured into saturated sodium bicarbonate solution, extracted several times with dichloromethane and the combined organic extracts are dried over sodium sulfate. The mixture is concentrated and the crude product obtained is purified by chromatography on about 500 ml of fine silica gel using a gradient system composed of n-hexane and ethyl acetate. In addition to 18% of starting material, 1.37 g (2.37 mmol, 64%) of the title compound are isolated as a colorless oil.

1 H-NMR (CDCI3): δ = 0.75-1, 37 (10H), 1.42-1, 88 (14H), 1.96-2.59 (10H), 2.70 (3H), 3.17-3.59 (3H), 3.72-4.31 (6H), 4.47-4.83 (1H), 5.04-5.53 (2H), 6.42-6 , 62 (1H), 6.97 (1H) ppm. example 1

(3S, 6R, 7R, 8E, 12E / Z.15S, 16E) -1, 3,15-tris - [[dimethyl (1, 1 - dimethylethyl) silyl] oxy] -17- (2-methyl-4- thiazolyl) -7- (tetrahydropyran-2-yloxy) -4,4,6,8,12,16-hexamethyl-heptadeca-8,12,16-trien-5-one The solution of 1.37 g mg (2nd , 37 mmol) of the compound shown in Example 1o in 60 ml of anhydrous dichloromethane is cooled to -78 ° C. under an atmosphere of dry argon, mixed with 9.4 ml of 2,6-lutidine, 9.3 ml of tert-butyldimethylsilyl trifluoromethanesulfonate and stir for 3 hours. It is poured into saturated sodium bicarbonate solution and extracted several times with dichloromethane. The combined organic extracts are dried over sodium sulfate and concentrated in vacuo. After column chromatography on silica gel with a gradient system of n-hexane and ethyl acetate, 2.07 g (2.25 mmol, 95%) of the title compound is isolated as a colorless oil. 1 H NMR (CDCI ₃ ): δ = -0.05-0.13 (18H), 0.82-0.95 (30H), 1, 03-1, 24 (6H), 1, 39-2 , 36 (23H), 2.71 (3H), 3.26 (1H), 3.33-4.29 (7H), 4.45-4.63 (1H), 5.12 (1H ), 5.31 (1H), 6.44 (1H), 6.91 (1H) ppm.

Example 1q

(3S, 6R, 7R, 8E, 12E / Z, 15S, 16E) -3,15-bis - [[dimethyl (1, 1-dimethylethyl) silyl] oxy] -1-hydroxy-17- (2-methyl- 4-thiazolyl) -7-

(tetrahydropyran-2-yloxy) -4,4,6,8, 12, 16-hexamethyl-heptadeca-8, 12,16-trien-5-one

Analogously to Example 10, 2.07 g (2.25 mmol) of the compound shown in Example 1 p is reacted at -20 ° C. and, after workup and purification, 783 mg (0.97 mmol, 43%) of the title compound is isolated as colorless oil.

¹ H-NMR (CDCI3): δ = 0.00-0.17 (12H), 0.87-0.98 (21 H), 1, 09-1, 30 (6H), 1, 44-2, 36 (24H), 2.71 (3H), 3.27 (1H), 3.50 (1H), 3.66 (2H), 3.86 (1H), 3.98-4.14 (2H), 4.25 (1H), 4.51 +4.62 (1H), 5.13 (1H), 5.33 (1H), 6.46 (1H), 6, 93 (1H) ppm. Example 1 r

(3S, 6R, 7R, 8E, 12E / Z.15S, 16E) -3,15-bis - [[dimethyl (1, 1-dimethylethyl) silyl] oxy] -17- (2-methyl-4-thiazolyl) -5-oxo-7- (tetrahydropyran

2-yloxy) -4,4,6,8,12,16-hexamethyl-heptadeca-8,12,16-trienal In analogy to example 1e, 783 mg (0.97 mmol) of the compound shown in example 1q is reacted and isolated after working up and purification, 874 mg (max. 0.97 mmol) of the title compound as a crude product, which is reacted further without purification.

Example 1s

(3S, 6R, 7R, 8E, 12Z, 15S, 16E) -3,15-bis - [[dimethyl (1, 1-dimethylethyl) silyl] oxy] - 17- (2-methyl-4-thiazolyl) -5 -oxo-7- (tetrahydropyran-2-yloxy) -4,4,6,8,12,16-hexamethyl-heptadeca-8,12,16-trienoic acid (A) and

(3S, 6R, 7R, 8E, 12E, 15S, 16E) -3,15-bis - [[dimethyl (1, 1-dimethylethyl) silyl] oxy] - 17- (2-methyl-4-thiazolyl) -5 -oxo-7- (tetrahydropyran-2-yloxy) -4,4,6,8,12,16-hexamethyl-heptadeca-8,12,16-trienoic acid (B)

The solution of 818 mg (max. 0.97 mmol) of that shown in Example 1 r

Compound in 30 ml of acetone is cooled to -30 ° C., mixed with 1.17 ml of a standardized 8N chromosulfuric acid solution and stirred for 1.5 hours. It is poured into a mixture of water and diethyl ether, the organic is washed

Phase with saturated sodium chloride solution and dries over sodium sulfate.

After filtration and removal of the solvent, 199 mg (242 μmol, 25%) of the title compound A and 219 mg (267 μmol, 28%) of the titite compound B are each isolated as a pale yellow oil. ¹ H-NMR (CDCI ₃ ) of A: δ = -0.03-0.12 (12H), 0.88 (18H), 1, 00-1, 29 (10H),

1, 43-2.53 (12H), 1.53 (3H), 1.68 (3H), 1.95 (3H), 2.72 (3H), 3.26 (1H), 3.37 -3.54

(1H), 3.71-3.91 (1H), 4.04 + 4.28 (1H), 4.12 (1H), 4.35 (1H), 4.50 + 4 , 61 (1H), 5.17

(1H), 5.24-5.42 (1H), 6.55 (1H), 6.94 (1H) ppm.

¹ H NMR (CDCI ₃ ) of B: δ = -0.02-0.14 (12H), 0.90 (18H), 0.98-2.38 (31 H), 2.47 (1 H ), 2.72 (3H), 3.24 (1H), 3.37-3.54 (1H), 3.71-3.90 (1H), 3.98-4.37 (3H ),

4.50 + 4.60 (1H), 5.13 (1H), 5.22-5.39 (1H), 6.47 (1H), 6.92 (1H) ppm.

Example 1t (3S, 6R, 7R, 8E, 12Z, 15S, 16E) -3 - [[Dimethyl (1, 1-dimethylethyl) silyl] oxy] -15-hydroxy-17- (2-methyl-4-thiazolyl) -5 -oxo-7- (tetrahydropyran-2-yloxy) - 4,4,6,8,12,16-hexamethyl-heptadeca-8, 12, 16-trienoic acid

In analogy to example 1 k, 199 mg (242 μmol) of compound A shown in example 1s is reacted and, after workup, 209 mg (max.

242 μmol) of the title compound as a crude product, which is reacted further without purification. H-NMR (CDCI ₃ ): δ = 0.02-0.15 (6H), 0.81-1, 89 (27H), 1.95-2.49 (9H), 1.98

(3H), 2.71 (3H), 2.96 (1H), 3.22 (1H), 3.30-3.54 (3H), 3.69-3.89 (1H), 4 , 00-4.27 (2H), 4.33 (1H), 4.50 + 4.60 (1H), 5.12-5.37 (2H), 6.64 + 6.68 (1st H), 6.95 (1H) ppm.

Example 1 u

(4S, 7R, 8R, 9E, 13Z, 16S (E)) - 4 - [[Dimethyl (1, 1-dimethylethyl) silyl] oxy] -16- (1 - methyl-2- (2-methyl-4- thiazolyl) ethenyl) -1-oxa-5,5,7,9,13-pentamethyl-8- (tetrahydropyran-2-yloxy) cyciohexadeca-9,13-diene-2,6-dione

The solution of 10 mg (14 μmol) of the compound shown in Example 1t in a mixture of 0.1 ml of anhydrous tetrahydrofuran and 2 ml of toluene is mixed with 3 μl of triethylamine, 2 μl of 2,4,6- Trichlorobenzoyl chloride and stirred for 1.5 hours at 23 ° C. The solution thus obtained is added dropwise to the boiling solution of 1 1 mg of 4-dimethylaminopyridine in 4 ml of toluene within 3 hours and the mixture is stirred for a further 30 minutes. The mixture is concentrated, taken up in a little dichloromethane and purified by chromatography on an analytical thin-layer plate using a gradient system composed of n-hexane and ethyl acetate. 2 mg (2.9 μmol, 21%) of the title compound are isolated as a colorless oil.

¹ H-NMR (CDCI3): δ = 0.09-0.21 (6H), 0.92 (9H), 1, 02-1, 33 (9H), 1, 46-2.67 (18H), 2.10 (3H), 2.72 (3H), 3.16 (1 H), 3.38-3.55 (1 H), 3.72-3.90 (1 H), 4.06- 4.37 (2H), 4.50 + 4.62 (1H), 5.21-5.40 (2H), 5.60 + 5.67 (1H), 6.58 (1H), 6.93 (1H) ppm.

example 1 (4S, 7R, 8R, 9E, 13Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5,7,9,13-pentamethyl-cyclohexadeca-9,13-diene-2,6-dione

The solution of 5.5 mg (8.0 μmol) of the compound shown in Example 1u in 0.5 ml of anhydrous tetrahydrofuran is mixed at 0 ° C. under an atmosphere of dry argon with 70 μl of a hydrogen fluoride

Pyridine complex, allowed to warm to 23 ° C and stirred for 4 hours. It is poured into saturated sodium bicarbonate solution and extracted several times

Dichloromethane. The combined organic extracts are dried over sodium sulfate and concentrated in vacuo. After chromatography on an analytical thin layer plate with a mixture of n-hexane and

After elution, ethyl acetate is isolated with a mixture of dichloromethane and

Methanol 1.8 mg (3.7 μmol, 46%) of the title compound as a colorless oil.

1 H NMR (CDCI ₃ ): δ = 1.18 (3H), 1.24 (3H), 1.30 (3H), 1.69 (3H), 1.70 (3H), 2.06 ( 3H), 2.11-2.47 (7H), 2.57 (1H), 2.70 (3H), 3.19 (1H), 3.78 (1H), 4.21 (1st H), 4.30

(1H), 5.17 (1H), 5.29 (1H), 5.35 (1H), 6.52 (1H), 6.95 (1H) ppm.

Example 2

(4S, 7R, 8R, 9E, 13E, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5,7,9,13-pentamethyl-cyclohexadec-9,13-diene-2,6-dione

Example 2a

(3S, 6R, 7R, 8E, 12E, 15S, 16E) -3 - [[Dimethyl (1, 1-dimethylethyl) silyl] oxy] -15-hydroxy-17- (2-methyl-4-thiazolyl) -5 -oxo-7- (tetrahydropyran-2-yloxy) - 4,4,6,8,12,16-hexamethyl-heptadeca-8, 12, 16-trienoic acid

Analogously to Example 1 k, 209 mg (255 μmol) of the compound B shown in Example 1s is reacted and, after workup, 224 mg (max. 255 μmol) of the title compound is isolated as a crude product, which is reacted further without purification.

¹ H-NMR (CDCI ₃ ): δ = 0.02-0.15 (6H), 0.79-1, 06 (18H), 1.06-2.19 (16H), 1.98 (3H) , 2.22-2.48 (4H), 2.72 (3H), 2.97 (1H), 3.22 (1H), 3.30-3.57 (2H), 3.70- 3.89 (1H), 4.00-4.42 (3H), 4.51 + 4.60 (1H), 5.18-5.40 (2H), 6.57 + 6.71 (1H) , 6.94 (1H) ppm.

Example 2b (4S, 7R, 8R, 9E, 13E, 16S (E)) - 4 - [[Dimethyl (1, 1-dimethylethyl) silyl] oxy] -16- (1 - methyl-2- (2-methyl- 4-thiazolyl) ethenyl) -1-oxa-5,5,7,9,13-pentamethyl-8- (tetrahydropyran-2-yloxy) cyclohexadeca-9,13-diene-2,6-dione

Analogously to Example 1 u, 224 mg (255 μmol) of the compound shown in Example 2a is reacted and, after workup and purification, 40 mg (58 μmol, 23%) of the title compound are isolated.

¹ H NMR (CDCI ₃ ): δ = 0.10 (3H), 0.22 (3H), 0.91 (9H), 1.05 (3H), 1.12 (3H), 1.17 + 1.27 (3H), 1.42-2.22 (10H), 1.47 + 1.60 (3H), 1.62 (3H), 2.12 (3H), 2.28-2.52 (4H), 2.69 (3H), 3.12 (1H), 3.46 (1H), 3.81 (1H), 4.08 + 4.28 (1H), 4.38 (1H), 4.48 + 4.57 (1H), 5.11 (1H), 5.20-5.40 (2H), 6.53 (1H), 6.91 (1H ) ppm.

Example 2

(1 S, 2E, 6E, 9S (E), 13S, 16R) -9- (1 -methyl-2- (2-methyl-4-thiazolyl) ethenyl) -

2,6,14,14,16-pentamethyl-10,17-dioxabicyclo [11.3.1] heptadec-2,6-diene

11, 15-dione (A) (4S, 7R, 8Z, 10E, 13E, 16S (E)) - 4-hydroxy-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 1-oxa-5,5,7,9,13-pentamethyl-cyclohexadec-8,10,13-triene-

2.6-dione (B)

(4S, 7R, 8E, 10E, 13E, 16S (E)) - 4-hydroxy-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5.5, 7,9,13-pentamethyl-cyclohexadec-8,10,13-triene-2,6-dione (C)

(4S, 7R, 8R, 9E, 13E, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5,7,9,13-pentamethyl-cyciohexadec-9,13-diene

2,6-dione (D)

The solution of 29 mg (42 μmol) of the compound shown in Example 2b in 3.0 ml of anhydrous tetrahydrofuran is added at 0 ° C. under a

Atmosphere of dry argon with 400 μl of a hydrogen fluoride-pyridine

Complex, allowed to warm to 23 ° C and stirred for 5 hours. You give more 100 μl of hydrogen fluoride-pyridine complex, react for another hour, pour into saturated sodium bicarbonate solution and extract several times

Dichloromethane. The combined organic extracts are dried over

Sodium sulfate and concentrated in vacuo. After chromatography on an analytical thin-layer plate with a mixture of n-hexane and

After elution, ethyl acetate is isolated with a mixture of dichloromethane and

Methanol 13 mg (27.6 μmol, 66%) of the title compound A, 0.5 mg (1.1 μmol, 3%) of the title compound B, 1.0 mg (2.1 μmol, 5%) of the title compound C and 0.1 mg (0.2 μmol, 0.5%) of the title compound D. 'H-NMR (CDCI ₃ ) of A: δ = 0.87 (3H), 1.02 (3H), 1, 18 (3H), 1.59 (3H), 1.53

3H), 1.95-2.40 (6H), 2.09 (3H), 2.49 (1H), 2.59 (1H), 2.71 (3H), 2.79 (1H), 3 , 45

1H), 3.71 (1H), 5.10 (1H), 5.33 (1H), 5.43 (1H), 6.58 (1H), 6.96 (1H) ppm.

H-NMR (CDCI3) of B: δ = 0.98 (3H), 1.15 (3H), 1.18 (3H), 1.73 (3H), 1.82

3H), 2.11 (3H), 2.30-2.54 (3H), 2.60 (1H), 2.71 (3H), 2.83 (2H), 3.02 (1H), 4 , 29 (1H), 4.46 (1H), 5.13 (1H), 5.21 (1H), 5.51 (1H), 5.89 (1H), 6.42 (1H), 6, 56 (1H),

6.98 (1H) ppm.

H NMR (CDCI ₃ ) of C: δ = 1.09 (3H), 1.13 (3H), 1.37 (3H), 1.66 (3H), 1.92

3H), 2.03 (3H), 2.10 (1H), 2.28 (1H), 2.43 (1H), 2.53 (1H), 2.62-2.76 (2H), 2 , 70

3H), 3.33 (1H), 3.94-4.12 (2H), 5.03 (1H), 5.13 (1H), 5.24 (1H), 5.70 (1H), 5 , 97 (1H), 6.43 (1H), 6.93 (1H) ppm.

MS (Fab thioglycerin) of D: m / z = 598 (M + 1 + 108), 490 (M + 1)

Claims

claims 1. epothilone derivatives of the general formula I,

wherein _R 1 a _{j R} 1 b are the same or different and are hydrogen, Cι-C- | Q-alkyl, aryl, C7-C2fj-aralkyl, or together a - (CH2) _m group with m = 1, 2, 3, 4 or 5, a - (CH2) -O- (CH2) group, R2 ^a , R2b are the same or different and are hydrogen, Cj-Ci Q-alkyl, aryl, C7-C20-aralkyl or together a - (CH2) n group with n = 2, 3, 4 or 5, G'-G-E-E 'a group

R ^3a r10 OH R ^3a HO HR ^3a H OH R ^3a R ⁴ I I I I I I I I I I I C - C - C - CH, C - C - C - CH, C - C - C - CH, C = C - C = CH, _R > 33 _b b _R 4 _H l ² _R 1 ₃ 3 _b b _R 1 ₄ 4 _H l ² _R ι ₃ 3 _h b _R ι ₄ 4 _H l ² _H l ² _R 3a is hydrogen, Ci -C- | Q-alkyl, aryl, C7-C-20-aralkyl, R ⁴ hydrogen, OR ^14a , shark, OSθ2R ^14b , _R 3b OPG ¹⁴ or R b, Rl ^4a together form a bond, 2H the hydrogen isotope deuterium, ³ H the hydrogen isotope tritium, R ^{4 is} hydrogen, CjCi Q-alkyl, aryl, C7-C20-aralkyl, R ⁵ is hydrogen, C ^«| -C- | o-alkyl, aryl, C7-C20-aralkyl, (CH2) _S -A wherein s is 1, 2, 3 or 4, A represents OR22 or shark, R22 represents hydrogen or PG ⁴ , RÖ, R ⁷ each represent a hydrogen atom, together an additional bond or an oxygen atom, R ⁸ hydrogen, C <| -C20-alkyl, aryl, C7-C20-aralkyl, which can all be substituted, X one oxygen atom, two alkoxy groups OR2 ³ , a C2-C- | o-alkylene-α, ω-dioxy group, which may be straight-chain or branched, H / OR9 or a grouping CR10R11, where R2 ³ for a C 1 -C 20 -alkyl radical, R ^ for hydrogen or a protective group PG ^X , R10, R11 are identical or different and represent hydrogen, a C- | -C20-alkyl, aryl, C7-C20-aralkyl radical or RIO and R11 together with the methylene carbon atom together represent a 5- to 7-membered carbocyclic ring, Y is an oxygen atom or two hydrogen atoms, Z is an oxygen atom or H / OR ^', 2 _ι where R12 is hydrogen or a protective group PG ^Z , including all stereoisomers of these compounds and mixtures thereof. 2. Compounds of general formula I according to claim 1, namely ^Λ (4S, 7R, 8R, 9E, 13Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5,7,9,13-pentamethyl-cyclohexadeca-9,13-diene-2,6-dione (4S, 7R, 8R, 9E, 13E, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5,7,9,13-pentamethyl-cyclohexadeca-9,13-diene-2,6-dione (1 S, 2E, 6E, 9S (E), 13S, 16R) -9- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 2,6, 14,14, 16-pentamethyl-10,17-dioxabicyclo [11.3.1] heptadec-2,6-diene-11, 15-dione (4S, 7R, 8Z, 10E, 13E, 16S (E)) - 4-hydroxy-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5, 7,9,13-pentamethyl-cyclohexadec-8,10,13-triene-2,6-dione (4S, 7R, 8E, 10E, 13E, 16S (E)) - 4-hydroxy-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5, 7,9,13-pentamethyl-cyclohexadec-8,10,13-triene-2,6-dione (1S, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -8.8 , 10,12,16-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione (1 R, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -8, 8,10,12,16-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione (1S, 3S (E), 7S, 10R, 11 R, 12E, 16S) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -8.8 , 10,12,16-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadec- 12-en-5,9-dione (1 S, 3S (E), 7S, 10R, 11 R, 12RS, 14RS, 17R) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 8,8,10,12,17-pentamethyl-4,13,18-trioxatricyclo [15.1.0.0 ^{12 '14} ] octadecane-5,9-dione (1 RS, 2R, 3R, 6S, 10S (E), 12Z, 16RS) -2,6-dihydroxy-10- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1, 3rd , 5,5,13-pentamethyl-9,17-dioxabicyclo [14.1.0] heptadec-12-en-4,8-dione (4S, 7R, 8R, 9E, 13Z, 16S (E)) - 4,8-Dihydroxy-7-ethyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1- oxa-5,5,9,13-tetramethyl-cyclohexadeca-9,13-diene-2,6-dione (4S, 7R, 8R, 9E, 13E, 16S (E)) - 4,8-dihydroxy-7-ethyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1- oxa-5,5,9,13-tetramethyl-cyclohexadeca-9,13-diene-2,6-dione (1S, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-10-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione (1 R, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-10-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl ) -8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione (1S, 3S (E), 7S, 10R, 11R, 12E, 16S) -7,11-dihydroxy-10-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione (1 S, 3S (E), 7S, 10R, 11 R, 12RS, 14RS, 17R) -7,11-dihydroxy-10-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ) ethenyl) -8,8,12,17-tetramethyl-4,13,18- trioxatricyclo [15.1.0.0 ^12-14] octadecane-5,9-dione (1 RS, 2R, 3R, 6S, 10S (E), 12Z, 16RS) -2,6-dihydroxy-3-ethyl-10- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1,5,5,13-tetramethyl-9,17-dioxabicyclo [14.1.0] heptadec-12-en-4,8-dione (4S, 7R, 8R, 9E, 13Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-oxa-5,5,7, 9,13-pentamethyl-cyclohexadeca-9,13-diene-2,6-dione (4S, 7R, 8R, 9E, 13E, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-pyridyl) ethenyl) -1 - oxa-5,5,7, 9,13-pentamethyl-cyclohexadeca-9,13-diene-2,6-dione (1S, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-pyridyl) ethenyl) -8,8,10,12 , 16-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione (1 R, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-pyridyl) ethenyl) -8,8,10, 12,16-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione (1 S, 3S (E), 7S, 10R, 11 R, 12E, 16S) -7,11-dihydroxy-3- (1-methyl-2- (2-pyridyl) - 8,8,10,12, 16-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione (1 S, 3S (E), 7S, 10R, 11 R, 12RS, 14RS, 17R) -7,11-dihydroxy-3- (1-methyl-2- (2-pyridyl) ethenyl) -8.8, 10,12,17-pentamethyl-4,13,18- trioxatricyclo [15.1.0.0 ^12-14] octadecane-5,9-dione (1 RS, 2R, 3R, 6S, 10S (E), 12Z, 16RS) -2,6-dihydroxy-10- (1-methyl-2- (2-pyridyl) ethenyl) -1, 3.5.5 , 13-pentamethyl-9,17-dioxabicyclo [14.1.0] heptadec-12-en-4,8-dione (4S, 7R, 8R, 9E, 13Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5- (1,3-trimethylene) -7,9,13-trimethyl-cyclohexadeca- 9,13-diene-2,6-dione (4S, 7R, 8R, 9E, 13E, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5- (1,3-trimethylene) -7,9,13-trimethyl-cyclohexadeca- 9,13-diene-2,6-dione (1 S, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -8, 8- (1,3-trimethylene) -10,12,16-trimethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione (1 R, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -8, 8- (1,3-trimethylene) -10,12,16-trimethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione (1S, 3S (E), 7S, 10R, 11 R, 12E, 16S) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -8.8 - (1,3-trimethylene) -10,12,16-trimethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione (1 S, 3S (E), 7S, 10R, 11 R, 12RS, 14RS, 17R) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyI) ethenyl) - 8.8- (1,3-trimethylene) -10,12,17-trimethyl-4,13,18-trioxatricyclo [15.1.0.0 ^12'14 ] octadecane-5,9-dione (1 RS, 2R, 3R, 6S, 10S (E), 12Z, 16RS) -2,6-dihydroxy-10- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -5.5 -trimethylene-1, 3,13-trimethyl-9,17-dioxabicyclo [14.1.0] heptadec-12-en-4,8-dione (4S, 7R, 8R, 9E, 13Z, 16S (E)) - 4,8-dihydroxy-7-ethyl-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-oxa-5, 5,9,13-tetramethyl-cyclohexadeca-9,13-diene-2,6-dione (4S, 7R, 8R, 9E, 13E, 16S (E)) - 4,8-dihydroxy-7-ethyl-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-oxa-5, 5,9,13-tetramethyl-cyclohexadeca-9,13-diene-2,6-dione (1S, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-10-ethyl-3- (1-methyl-2- (2-pyridyl) ethenyl) -8.8 , 12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en- 5,9-dione (1 R, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-10-ethyl-3- (1-methyl-2- (2-pyridyl) ethenyl) -8, 8, 12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-ene-5,9-dione (1 S, 3S (E), 7S, 10R, 11 R, 12E, 16S) -7,11-dihydroxy-10-ethyl-3- (1-methyl-2- (2-pyridyl) -8.8, 12,16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione (1S, 3S (E), 7S, 10R, 11 R, 12RS, 14RS, 17R) -7,11-dihydroxy-10-ethyl-3- (1-methyl- 2- (2-pyridyl) -8,8,12,17-tetramethyl-4,13,18- trioxatricyclo [15.1.0.0 ^12-14] octadecane-5,9-dione (1 RS, 2R, 3R, 6S, 10S (E), 12Z, 16RS) -2,6-dihydroxy-3-ethyl-10- (1-methyl-2- (2-pyridyl) ethenyl) -1.5 , 5,13-tetramethyl-9,17-dioxabicyclo [14.1.0] heptadec-12-ene-4,8-dione (4S, 7R, 8R, 9E, 13Z, 16S (E)) - 4,8-Dihydroxy-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-oxa-5,5- (1st , 3-trimethylene) -7,9,13-trimethyl-cyclohexadeca-9,13-diene-2,6-dione (4S, 7R, 8R, 9E, 13E, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-pyridyl) ethenyl) -1 - oxa-5,5- (1st , 3-trimethylene) -7,9,13-trimethyl-cyclohexadeca-9,13-diene-2,6-dione (1 S, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-pyridyl) ethenyl) -8.8- (1st , 3-trimethylene) -10,12,16-trimethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione (1 R, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-pyridyl) ethenyl) -8.8- (1st , 3-trimethylene) -10,12,16-trimethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione (1S, 3S (E), 7S, 10R, 11 R, 12E, 16S) -7,11-dihydroxy-3- (1-methyl-2- (2-pyridyl) ethenyl) -8.8- (1, 3-trimethylene) -10,12,16-trimethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione (1 S, 3S (E), 7S, 10R, 11 R, 12RS, 14RS, 17R) -7,11-dihydroxy-3- (1-methyl-2- (2-pyridyl) ethenyl) -8.8- (1, 3-trimethylene) -10,12,17-trimethyl-4,13,18- trioxatricyclo [15.1.0.0 ^12-14] octadecane-5,9-dione (1 RS, 2R, 3R, 6S, 10S (E), 12Z, 16RS) -2,6-dihydroxy-10- (1-methyl-2- (2-pyridyl) ethenyl) -5,5-trimethylene-1 , 3,13-trimethyl-9,17-dioxabicyclo [14.1.0] heptadec-12-en-4,8-dione (4S, 7R, 8R, 9E, 13Z, 16S (E)) - 4,8-dihydroxy-16- (2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5,5,7, 9,13-pentamethyl-cyclohexadeca-9,13-diene-2,6-dione (4S, 7R, 8R, 9E, 13E, 16S (E)) - 4,8-dihydroxy-16- (2- (2-methyl-4-thiazolyI) ethenyl) -1-oxa-5,5,7, 9,13-pentamethyl-cyclohexadeca-9,13-diene-2,6-dione (1S, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-3- (2- (2-methyl-4-thiazolyl) ethenyl) -8.8, 10.12 , 16-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione (1 R, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-3- (2- (2-methyl-4-thiazolyl) ethenyl) -8,8,10, 12,16-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione (1 S, 3S (E), 7S, 10R, 11 R, 12E, 16S) -7,11-dihydroxy-3- (2- (2-methyl-4-thiazolyl) ethenyl) -8,8,10, 12,16-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione (1 S, 3S (E), 7S, 10R, 11 R, 12RS, 14RS, 17R) -7,11-dihydroxy-3- (2- (2-methyl-4-thiazolyl) ethenyl) -8.8, 10,12,17-pentamethyl-4,13,18- trioxatricyclo [15.1.0.0 ^12-14] octadecane-5,9-dione (1 RS, 2R, 3R, 6S, 10S (E), 12Z, 16RS) -2,6-dihydroxy-10- (2- (2-methyl-4-thiazolyl) ethenyl) -1, 3.5.5 , 13-pentamethyl-9,17-dioxabicyclo [14.1.0] heptadec-12-en-4,8-dione (4S, 7R, 8R, 9E, 13Z, 16S (E)) - 4,8-dihydroxy-16- (2- (2-pyridyl) ethenyl) -1-oxa- 5,5,7,9, 13- pentamethyl-cyclohexadeca-9,13-diene-2,6-dione (4S, 7R, 8R, 9E, 13E, 16S (E)) - 4,8-dihydroxy-16- (2- (2-pyridyl) ethenyl) -1-oxa- 5,5,7,9, 13- pentamethyl-cyclohexadeca-9,13-diene-2,6-dione (1 S, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-3- (2- (2-pyridyl) ethenyl) - 8,8,10,12,16- pentamethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione (1 R, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7, 11 -dihydroxy-3- (2- (2-pyridyl) ethenyl) - 8,8,10,12, 16- pentamethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione (1 S, 3S (E), 7S, 10R, 11 R, 12E, 16S) -7,11-dihydroxy-3- (2- (2-pyridyl) ethenyl) - 8,8,10,12,16- pentamethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione (1 S, 3S (E), 7S, 10R, 11 R, 12RS, 14RS, 17R) -7,11-dihydroxy-3- (2- (2-pyridyl) ethenyl) -8,8,10,12, 17-pentamethyl-4, 13,18-trioxatricyclo [15.1.0.0 ^{12 14} ] octadecane-5,9-dione (1 RS, 2R, 3R, 6S, 10S (E), 12Z, 16RS) -2,6-dihydroxy-10- (2- (2-pyridyl) ethenyl) -1,3,5,5,13-pentamethyl -9, 17-dioxabicyclo [14.1.0] heptadec-12-en-4,8-dione (4S, 7R, 8R, 9E, 13Z, 16S (E)) - 4,8-dihydroxy-7-ethyl-16- (2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5,9,13-tetramethyl-cyclohexadeca-9,13-diene-2,6-dione (4S, 7R, 8R, 9E, 13E, 16S (E)) - 4,8-dihydroxy-7-ethyl-16- (2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5,9,13-tetramethyl-cyclohexadeca-9,13-diene-2,6-dione (1 S, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-10-ethyl-3- (2- (2-methyl-4-thiazolyl) ethenyl) -8, 8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione (1 R, 3S (E), 7S, 10R, 11 R, 12E, 16R) -7,11-dihydroxy-10-ethyl-3- (2- (2-methyl-4-thiazolyl) ethenyl) -8, 8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione (1 S, 3S (E), 7S, 10R, 11 R, 12E, 16S) -7,11-dihydroxy-10-ethyl-3- (2- (2-methyl-4-thiazolyl) ethenyl) -8, 8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadec-12-en-5,9-dione (1 S, 3S (E), 7S, 10R, 11 R, 12RS, 14RS, 17R) -7,11-dihydroxy-10-ethyl-3- (2- (2-methyl-4-thiazoiyl) ethenyl) - 8,8, 12,17-tetramethyl-4, 13,18-trioxatricyclo [15.1.0.0 ^12'14 ] octadecane-5,9-dione (1 RS, 2R, 3R, 6S, 10S (E), 12Z, 16RS) -2,6-dihydroxy-3-ethyl-10- (2- (2-methyl-4-thiazolyl) ethenyl) -1, 5 , 5,13-tetramethyl-9,17-dioxabicyclo [14.1.0] heptadec-12-ene-4,8-dione 3. A process for the preparation of the epothilone derivatives of the general formula I according to claim 1

I, wherein the substituents have the meanings given in the general formula I, characterized in that a fragment of the general formula A

wherein R ^1a ', R ^1', R 2a 'R 2b nd _U' b the already for Rl ^a, Rl, _R 2a _R 2b _un d mentioned Have meanings and R ¹³ CH ₂ ORl, CH ₂ -Hal, CHO, CO ₂ R ^13b , COHal, R ¹⁴ hydrogen, OR ^14a , shark, OSO ₂ R ^4b , R ^13a , R ^14a hydrogen, Sθ2-alkyl, SO2-A1 I, Sθ2-aralkyl or together a - (CH2) o group or together a CR ¹ 5a _R 15b group, _R 13b _R 14b hydrogen, C- | -C2Q-alkyl, aryl, C <| -C2Q-aralkyl, F ^ lδa, 15b are the same or different and are hydrogen, CjCi Q-alkyl, aryl, C7-C20-aralkyl, or together a - (CH2) q group, shark halogen, o 2 to 4, q 3 to 6, with a fragment of formula B.

B where R ^3a 'and R5' have the meanings already mentioned for R ^3a and R ^, and V is an oxygen atom, two alkoxy groups OR ¹⁷ , a C2-C <ιo-alkylene-α, ω-dioxy group, which can be straight-chain or branched or H / OR16, W is an oxygen atom, two alkoxy groups OR ¹⁹ , a C-2-C-ιo-alkylene-α, ω-dioxy group, which can be straight-chain or branched, or H / OR 8, R16, R18 independently of one another hydrogen or one Protecting group PG ^″ R ¹⁷ , R19 independently of one another are C 1 -C 20 -alkyl, to a partial fragment of the general formula AB

FROM, where Rl ^a ', Rl b' _r

R2b ' _{ι R} 3a _ι R5, _R 13 _{7 R} 14_ _G , E, V and Z have the meanings already mentioned, implements and this partial fragment AB with a fragment of the general formula C

wherein R ³ 'has the meaning already given for R ³ in the general formula I and R ⁷ ' is a hydrogen atom, R20 is a hydrogen atom or a protective group PG2 R 1 is a hydroxyl group, halogen, a protected hydroxyl group OPG ³ , a phosphonium halide residue PPh3 ⁺ Hal ^" (Ph = phenyl; Hai = F, Cl, Br, I), a phosphonate residue P (O) (OQ) 2 (Q = C <| -C- | o-alkyl or phenyl ) or a phosphine oxide residue P (O) Ph2 (Ph = phenyl), U one oxygen atom, two alkoxy groups OR2 ³ , one C2-C- | Q-alkylene-α, ω-dioxy group, which can be straight-chain or branched, H / OR ⁹ or a grouping CR ^ ORI ^"1 , where R ²³ for a C- | -C20 alkyl radical, RÖ for hydrogen or a protective group PG ³ , R ^ O, Rl ^{1 are the} same or different and for hydrogen, a -C-C20-alkyl, aryl, C7-C20-aralkyl radical or R10 and Rl 1 together with the methylene carbon atom together for are a 5- to 7-membered carbocyclic ring, including all stereoisomers and mixtures thereof, and free hydroxyl groups are optionally etherified or esterified, free carbonyl groups are optionally ketalized, converted into an enol ether or reduced, and free acid groups in the salts of which may be converted with bases, to a partial fragment of the general formula ABC

ABC, wherein Rl ^a ', Rl', R2a ' _j

_R 3a _(R 5 _{> R} 6 _{f R} 7 _{f R} 8, _R 13 _{j R} 14 _ι Q, E, U and Z have the meanings already mentioned, is implemented and this partial fragment of the general formula ABC is cyclized to an epothilone derivative of the general formula I. 4. Intermediates of the general formula B

B where R ^3a 'and R5' have the meanings already mentioned for R ^3a and R ^, and V is an oxygen atom, two alkoxy groups OR ^ ⁷ , a C2-CiQ-alkylene-α, ω-dioxy group, which can be straight-chain or branched or H / OR16, W one oxygen atom, two alkoxy groups OR ^, one C-2-C-jo-alkylene-α, ω-dioxy group, which can be straight-chain or branched, or H / OR1S, R16, R ^ independently of one another hydrogen or one Protection group PG ^' ' _R 17 _{) R} 19 independently of one another C- _| -C20 alkyl. 5. Intermediates of the general formula AB

FROM, wherein R ^{1 a} ', R ^{1 b} ', R2a '_>

_R 3a _{f R} 5 _{f R} 13_ _R 14 _{> Gj E> v} and Z have the meanings already mentioned and PG ^{14 represents} a hydrogen atom or a protective group PG. 6. Intermediates of the general formula ABC

ABC, wherein Rl ^a ', Rl', R23 ', _R 2b' _{t R} 3a _{t R} 5 _{τ R} 6 _ι R7, R8 _JR 13 _JR 14 _f Q, E, U and Z have the meanings already mentioned. 7. Pharmaceutical preparations containing at least one compound of general formula I according to claim 1 and a pharmaceutically acceptable carrier. 8. Use of the compounds of general formula I according to claim 1 for the manufacture of medicaments.