WO2000000485A1 - Epothilon derivatives, their preparation process, intermediate products and their pharmaceutical use - Google Patents

Abstract

The invention relates to new epothilon derivatives of general formula (I) where the substituents Y, Z, R?1a, R1b, R2a, R2b, R3, R4a, R4b¿, D-E, R?5, R6, R25, R7, R8¿ et X have the meaning given in the description. These new compounds co-operate with tubulin by stabilising formed microtubuli. They are able to affect cell splitting in a phase-specific way and are useful for the treatment of malignant tumours, such as ovarian, stomach, colon, lung, head or neck cancer, adenocarcinoma, malignant melanoma and acute lymphoid and myeloid leukaemia. They are also adapted to anti-angiogenesis therapy and to treatment of chronic inflammation diseases (psoriasis, arthritis). These new compounds can be applied on polymer materials or introduced therein to avoid uncontrolled proliferation on medical implants and to improve tolerance of these medical implants. The inventive compounds can be used alone or in combination with other ingredients or classes of substances which can be used in tumour therapy to obtain respectively additional actions or synergistic effects.

Description

 Epothilone derivatives, processes for their preparation, intermediates and their pharmaceutical use

By Höfle et ai. the cytotoxic effects of the natural substances Epothiion A (R hydrogen) and Epothilon B (R = methyl)

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

e.g. in Angew. Chem. 1996, 108, 1671-1673. This is novel 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 and their physical properties compared to taxol, e.g. a water solubility that is 30 times higher 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 done by improving the selectivity of the action and / or reducing undesirable toxic side effects and / or increasing the potency.

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 al. described in WO 97/19086. These derivatives were made from the natural epothion 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. Soc, Vol. 119, No. 34, 1997, pp. 7960 - 7973 as well as the synthesis of epothilones A and B and some epothilone

wherein

R5 ', R8' have the meaning already given in the general formula I for R5 and R ^ and R20 is a hydrogen atom or a protective group PG ^

U is an oxygen atom, two alkoxy groups OR ⁹ , a C2-C-ιo-alkylene-α, ω-dioxy group, which can be straight-chain or branched, H / OR ¹⁰ or one

Grouping CR ^{1 1} R ¹² , where

R9 represents a C 1 -C 20 -alkyl radical,

R10 for hydrogen or a protective group PG ^,

R ¹ 1, R12 are the same or different and are hydrogen, a C 1 -C 20 -alkyl, aryl, C7-C20-aralkyl radical or R ^{"1 1} and R ¹ together with the methylene carbon atom together for a 5- to 7-membered carbocyclic ring W is an oxygen atom, two alkoxy groups OR21, a C2-Cιrj-alkylene-α, ω-dioxy group, which can be straight-chain or branched or H / OR22, where

R21 is a C 1 -C 20 -alkyl radical,

R22 for hydrogen or a protective group PG ⁷ mean.

15. Intermediates of the general formula BC

wonn R3, R ^4a , R ^4b , R ⁵ , R ⁶ , R ²⁵ , R ⁷ , R ²⁰ , D, E, U and α V have the meanings already mentioned.

16. Intermediates of the general formula ABC

ABC,

wherein R ^a , R ^{1 b} , R ² a, R2b, _R 3 _t R4 _{3> R} 4b _ι RÖ, _R 6 _t R25, _R 7_ _R 8, R14 _R 15 _t D, E, U and Z have the meanings already mentioned to have.

17. Pharmaceutical preparations containing at least one compound of general formula I according to claim 1 and a pharmaceutically acceptable carrier.

18. Use of the compounds of general formula I according to claim 1 for the manufacture of medicaments.

Analogues in J. Am. Chem. Soc, Vol. 1 19, No. 34, 1997, pp. 7974-7991 also by Nicolaou et al. rubbed.

Nicolaou et al. describe in Angew. Chem. 1997, 109, No. 19, pp. 2181-2187 the preparation of epothiion A analogues by means of combinatorial solid phase synthesis. Some Epothiion 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 _R 1 b are the same or different and are hydrogen, C ^ -C- | o ^_ alkyl, aryl, C7-C20-aralkyl, or together a (CH2) _m group with m = 2, 3, 4 or 5,

R2a, R2b are the same or different and are hydrogen, C- | -Cι o-alkyl, aryl, C7-C20 aralkyl or together a - (CH2) _n group with n = 2, 3, 4 or 5,

R ^{3 is} hydrogen, C- | -C- | o-alkyl, aryl, C7-C20-aralkyl,

R ^4a , R ^{4b are the} same or different and are hydrogen, C 1 -C 8 -alkyl, aryl, C 7 -C 20 aralkyl or together a - (CH2) p group with p = 2, 3, 4 or 5 .

HO OH HO H

O I I I I

H ₂ C-CH, HC = CH c≡C _U J u ^{cc C} "~ ^C

DE a group ^HHHH

R ^{5 is} C-1 -C-1 o-alkyl, aryl, C7-C20 ralkyl,

R ⁶ , R ⁷ each represent a hydrogen atom, together an additional bond or an oxygen atom, R25 hydrogen, C- | -C- | o-alkyl, where the alkyl radical can optionally be substituted by one or more halogen atoms and / or hydroxyl groups, R ^{8 is} hydrogen, C- | -C20-alkyl, aryl, C7-C20-araikyl, which can all be substituted, X one oxygen atom, two alkoxy groups OR ⁹ , one C2-C-ι o-alkylene, ω-dioxy group, which can be straight-chain or branched, H / OR ^ O or one

Grouping CR ^{1 1} R ² , where

R ⁹ for a C 1 -C 20 -alkyl radical, RIO for hydrogen or a protective group PG ¹ ,

R ^{1 1} , R ¹ 2 are the same or different and are hydrogen, a C 1 -C 20 -alkyl, aryl, C7-C20-aralkyl radical or R ^{1 1} and R ¹ 2 together with the methylene carbon atom together for a 5- to 7th -linked carbocyclic ring, Y is an oxygen atom or two hydrogen atoms,

Z is an oxygen atom or H / OR ^{1 3} , where R ^ ^{3 is} hydrogen or a protective group PG2, including all stereoisomers of these compounds and also mixtures thereof.

The presentation of the new epothilone derivatives is based on the linkage of three partial fragments A, B and C and is carried out in the same way as for epothilone A and epothilone B derivatives (ie there can only be one hydrogen atom in the place of R§) in WO 99/07692 is described. The interfaces are as indicated in the general formula I '.

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

A,

wherein R ^{1 a} ', R', R2a ' _{and R} 2b " _d j _e already have the meanings given for Ria, Rl b _t R2a _and j R2b and

R1 ⁴ CH ₂ OR ^{1 a} , CH ₂ -Hal, CHO, CO ₂ R ¹⁴ , COHal,

R15 hydrogen, OR ^15a , shark, OSO ₂ R ^15b ,

Rl4a _t Rl 5a hydrogen, Sθ2-alkyl, SO2-A17I, Sθ2-aralkyl or together a - (CH2) o group or together a CR ^16a R ¹ 6 group,

Rl4b _{t R} 15b hydrogen, -CC 20 alkyl, aryl, C ₇ -C ₂ o-aralkyl,

_R 16a _{t R} 16b are the same or different and are hydrogen, C <| -C- | o-alkyl, aryl. C7-C20 aralkyi, or together a - (CH2) π group,

Shark halogen, 0 2 to 4, q 3 to 6, including all stereoisomers and mixtures thereof, and etherified or esterified free hydroxyl groups in R ¹⁴ and R- ^, free carbonyl groups in

A and R ^ ⁴ 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 where

R ³ '. R ^4a ', R ^4b ' and R ^{25 have} the meanings already mentioned for R ³ , R a, R4b _{and R} 25, and

R ^{17 is} a hydroxy group, halogen, a protected hydroxy group OPG ³

Phosphonium halide residue PPh3 ⁺ Hal "(Ph = phenyl; Hai = F, Cl, Br, I) Phosphonate residue P (O) (O ^Q ) 2 (Q = C1-C1 o-alkyl or phenyl) or a

Phosphine oxide residue P (0) P 2 (Ph = phenyi), V one oxygen atom, two alkoxy groups OR ^{1 8} , one C2-C- | o-alkylene-α, ω-dioxy group, which can be straight-chain or branched or H / OR ¹⁹ , R18 C- _| -C ₂ o-alkyl,

R ^{19 represents} a hydrogen or a protective group PG ⁴ .

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

wherein

R ^{5 '} , R ⁸ ' have the meaning already given in general formula I for R ⁵ and R ⁸ and

R20 is a hydrogen atom or a protective group PG ^

U is an oxygen atom, two alkoxy groups OR ⁹ , a C2-C-ιo-alkyien-α, ω-dioxy group, which can be straight-chain or branched, H / OR ¹⁰ or a group CR ^{1 1} R ¹² , where

R ^{9 represents} a C 1 -C 20 -alkyl radical,

R ¹ ° for hydrogen or a protective group PG ⁶ ,

R ^{1 1} , R ¹ 2 are the same or different and are hydrogen, a C ¹ -C 20 -alkyl, aryl, C7-C20-aralkyl radical or R ^{1 1} and R ¹² together with the methylene carbon atom together for a 5th - to 7-membered carbocyclic ring W is an oxygen atom, two alkoxy groups OR ²¹ , a C2-C-ιo-alkylene-α, ω-dioxy group, which can be straight-chain or branched or H / OR ²² , where

R ^{21 represents} a C -C20 alkyl radical,

R ^{22 represents} hydrogen or a protective group PG ⁷ . As alkyl groups R ^{1 a} _, R ^{1 b} . _R 2a _{, R} 2b_ R3 _{| R} 4_ _R 5_ _R 16a _{t R} 16b _{and R} 25 _{are straight} . or branched-chain alkyl groups with 1-10 cone tensor atoms to oetractene, such as, for example, methyl. Ethyl, propyl, isopropyl. Butyl, isobutyl, tert-butyl. Pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl. As alkyl groups R ⁸ , R ⁹ , R ^{1 0} , R ^{1 1} , R * ² ; R ^{1 3,} Rt ^b, R 5b _and R 1 8 g _are to be regarded _he ad or verzweigtkertige alkyl groups having 1 -20 Kohlenstoffatomeπ; such as the residues mentioned by name in the preceding paragraph and their corresponding higher homologues.

The alkyl groups R ¹ a, b Rl, R 2a, _{R 2b> R} 3 _t R4_ _R 5 _{f R} 8 _{τ R} 9 _t 10 RH, R12_ _R 13 _{f R} 14b R ¹ 5 ^b, R _{6a) R} 16b _{and R} 18 may be perfluorinated or substituted by 1-5

Halogen atoms, hydroxyl groups, C- | -C4-alkoxy groups, Cß-C - ^ - aryl groups (which by

1-3 halogen atoms can be substituted).

As aryl radical Ri a, Rl b, _R 2 _{a> R} 2b, _R 3 _{t R} 4, _R 5, _R 8, R10, R1 1, R12, _R 13, _R 14b _R 15b,

R ^{1 8a} and R ^{1 8} come substituted and unsubstituted carbocyclic or heterocyclic radicals having one or more heteroatoms such as, for example, phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyi, pyrazinyi, quinolyi, thiazolyl, the single or multiple can be substituted by halogen, OH, O-alkyl, CO2H, CO ₂ -alkyl, -NH ₂ , -NO ₂ , -N3, -CN, C -C ₂ o-alkyl, C ^< | -C-20-acyl, Cj-C20-acyloxy groups, in question. The aralkyl groups in Rl ^a , Rl ^b , R ^2a , R ² , R ³ , R ⁴ , R5, R8, _R 10 _{t R} 1 1, _R 12_ _R 13_ _R 14b, 15b _{? R} 16a _and 16b can contain up to 14 carbon atoms, preferably 6 to 10, in the ring and 1 to 8, preferably 1 to 4, atoms in the alkyl chain. Examples of suitable aralkyl radicals are benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, pyridylpropyl. The rings can be mono- or polysubstituted by halogen, OH, O-alkyl, CO2H, CO 2 -alkyl, -NO2, -N3, -CN, C- | - C20-alkyl, C- | -C20-acyl, C- ι -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. Representing the protective groups PG are alkyl- and / or aryl-substituted silyl, C- | - C20-alkyl, C4-C7-cycioalkyl, which can additionally contain an oxygen atom in the ring, aryl, C7-C20-araikyl, C- C20 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. Easily removable alkyl or silyl radicals, such as, for example, are preferred from the corresponding alkyl and silyl ethers

Methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyi,

Trimethylsilyl-, triethylsiiyl-, tert-butyldimethyisilyl-, tert-butyldiphenylsilyl-, tribenzylsilyl-

Triisopropylsilyl, benzyi, para-nitrobenzyl, para-methoxybenzyl radical and

Alkylsulfoπyl- and arylsulfonyl residues. Examples of acyl radicals are formyl, acetyl, propionyl, Isopropionyl, pivalyi. Butyryl or Benzoyi, which can be substituted with amino and / or hydroxy groups, in question.

The acyro groups PG ^"1 and PG ² in R ^{" 1 0} and R ^{1 3} 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 R ^{1 b} is preferably 2, 3 or 4.

The C2-C- | o-Alkylene-α, ω-dioxy group is preferably an ethylene ketal or neopentyl keta group.

The radical R ²⁵ is preferably a hydrogen atom, a methyl, ethyl, propyl, hydroxymethyl, fluoromethyl or trifluoromethyl group.

The substituents in the compounds of general formula I can be chosen so that

R ³ , R ^4a , R ^4b , DE, R ⁵ , R ⁶ , R ²⁵ and R ^{7 can} all have the meanings given in general formula I, and the rest of the molecule is identical to the naturally occurring epothilone A or B. or

R ⁵ , R ⁶ , R ²⁵ , R ⁷ , R ⁸ and X can all have the meanings given in the general formula I, and the rest of the molecule is identical to the naturally occurring epothiion A or B or

Y, Z, R ^{1 a} , R ¹ , R ^2a , R ^2b , R ³ , R ⁴ a, R4b, _{D. Eι R} 5 _{t R} 6 _t R25 _{and R} 7 _a | _{ie d} j _e can have meanings given in the general formula I, and the rest of the molecule is identical to the naturally occurring epothilone A or B or

Y, Z, R ^{1 a} , Rl ^b , R ² a, R2b_ _R 5 _{t R} 6 _> R25 _J R7 ₍ R8 _{and X a} || _ed j _e may have meanings given in general formula I, and the rest of the molecule is identical to the naturally occurring epothilone A or B or

R ³ , R ^4a , R ^4b , DE, R ⁵ , R ⁶ , R ²⁵ , R ⁷ , R ⁸ and X can all have the meanings given in general formula I, and the rest of the molecule is identical to that which occurs naturally Epothilon A or B. A further variant according to the invention provides those compounds in which R ^ is stent for a methyl, ethyl or propylene group. wooei then preferably R ^ unα R ⁷ together mean an additional bond or an epoxy group.

The compounds mentioned below are preferred according to the invention:

(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5,7,9,14-pentamethyl-cyclohexadec-13-ene-2,6-dione

(1 S, 3S (E), 7S, 10R, 1 1 S, 12S, 16R) -7.1 1-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 1, 8,8,10,12-pentamethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and (1 R, 3S (E), 7S, 10R, 1 1 S, 12S, 16S ) -7.1 1 -Dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1, 8,8,10,12-pentamethyl-4, 17-dioxabicyclo [14.1. 0] heptadecane-5,9-dione

(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-oxazolyl) ethenyl) -1 - oxa-5, 5,7,9,14-pentamethyl-cyclohexadec-13-ene-2,6-dione

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

(1 R, 3S (E), 7S, 10R, 1 1 S, 12S, 16S) -7.1 1-dihydroxy-3- (1-methyl-2- (2-methyl-4-oxazolyl) ethenyl) - 1, 8,8,10, 12-pentamethyl-4,17-dioxabicyclo [14.1 .0] heptadecane-5,9-dione

(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-oxa- 5,5,7, 9, 14-pentamethyl-cyclohexadec-13-en-2,6-dione

(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-pyridyl) ethenyl) - 1, 8,8,10, 12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and (1 R, 3S (E), 7S, 10R, 1 1 S, 12S, 16S) -7,11-dihydroxy- 3- (1-methyl-2- (pyridyi) ethenyl) -1,8,8,10,12-pentamethyl-4,17-dioxabicyclo [14.1 .0] heptadecane-5,9-dione

(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-Dihydroxy-7-ethyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyi) -1 - oxa-5,5,9,14-tetramethyl-cyclohexadec-13-ene-2,6-dione

(1 S, 3S (E), 7S, 10R, 1 1 S, 12S, 16R) -7.1 1-dihydroxy-10-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyi) ) etheπyl) -1, 8,8,12-tetramethyl-4, 17-dioxabιcyclo [4.1 .0] heptadecane-5,9-dione and (1 R, 3S (E), 7S, 10R, 1 1 S, 12S, 16S) -7, 11 -dihydroxy-10-ethyl-3- (1-methyl-2- (2-methyl-4-thioazoiyl) ethenyi) -1.3.3.12-tetramethyl-4, 17-dioxabιcyclo [14.1.0] heptaαecan-5,9-αion

(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-Dihydroxy-5,5-dimethyien-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyi) - 1-oxa-7,9,14-trimethyl-cyclohexadec-13-ene-2,6-dione

(1 S, 3S (E), 7S, 10R, 11 S, 12S, 16R) -7, 11 -dihydroxy-8,8-dimethylene-3- (1-methyl-2- (2-methyl-4-thiazolyl ) ethenyl) -1, 10,12-trimethyl-4,17-dioxabicyclo [14.1.0] heptadecan-5,9-dione and (1 R, 3S (E), 7S, 10R, 11 S, 12S, 16S) -7,11-dihydroxy-8,8-dimethylene-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1, 10,12-trimethyl-4,17-dioxabicyclo [14.1. 0] heptadecane-5,9-dione

(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-5,5-trimethylene-16- {1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 1-oxa-7,9,14-trimethyl-cyclohexadec-13-ene-2,6-dione

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

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

(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-Dihydroxy-14-ethyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1- oxa-5,5,7,9-tetramethyl-cyclohexadec-13-ene-2,6-dione

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

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

(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-Dihydroxy-14-ethyl-16- (1-methyl-2- (2-methyl-4-oxazolyl) ethenyl) -1- oxa-5,5,7,9-tetramethyl-cyclohexadec-13-ene-2,6-dione

(1S, 3S (E), 7S, 10R, 11 S, 12S, 16R) -7,11-dihydroxy-1-ethyl-3- (1-methyl-2- (2-methyl-4-oxazolyl) ethenyi) -8,8,10,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and

(1 R, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-1-ethyl-3- (1-methyl-2- (2-methyl-4-oxazolyl) ethenyl) -8,8,10,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (4S, 7R.8S, 9S, 13Z.16S (E)) - 4,8-Dihydroxy-14-ethyl-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-oxa-5, 5.7,9-tetramethyl-cycionexadec-13-en-2,6-dione

(1 S, 3S (E), 7S, 10R, 1 1 S, 12S, 16R) -7.1 1 -dihydroxy-1-ethyl-3- (1-methyl-2- (2-pyridyl) ethenyl) - 8,8,10,12-tetramethyl-4, τ ^r -dioxabicyclo [14.1 .0] heptadecane-5,9-dione and (1 R, 3S (E), 7S, 10R, 1 1 S, 12S, 16S) -7.1 1 -Dihydroxy-1-ethyl-3- (1-methyl-2- (2-pyridyl) ethenyl) -8,8,10,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane -5,9-dione

(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-7,14-diethyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 1-oxa-5,5,9-trimethyl-cyclohexadec-13-ene-2,6-dione

(1 S, 3S (E), 7S, 10R, 1 1 S, 12S, 16R) -7.1 1-dihydroxy-1, 10-diethyl-3- (1-methyl-2- (2-methyl-4 - thiazoiyl) ethenyl) -8,8,12-trimethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and (1 R, 3S (E), 7S, 10R, 1 1 S, 12S , 16S) -7.1 1-dihydroxy-1, 10-diethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -8,8,12-trimethyl-4,17- dioxabicyclo [14.1.0] heptadecane-5,9-dione

(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-Dihydroxy-14-proyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1 - oxa-5,5,7,9-tetramethyl-cyciohexadec-13-en-2,6-dione

(1 S, 3S (E), 7S, 10R, 1 1 S, 12S, 16R) -7.1 1 -dihydroxy-1-propyl-3- (1-methyl-2- (2-methyl-4-thiazoiyi ) ethenyl) -8,8, 10,12-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and

(1 R, 3S (E), 7S, 10R, 1 1 S, 12S, 16S) -7.1 1-dihydroxy-1-propyl-16- (1-methyl-2- (2-methyl-4-thiazolyl ) ethenyl) -8,8,10,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione

(4S, 7R, 8S, 9S, 13E, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-thiazoiyl) ethenyl) -1-oxa-5, 5,7,9,14-pentamethyl-cyclohexadec-13-ene-2,6-dione

(1 S, 3S (E), 7S, 10R, 1 1 S, 12S, 16S) -7.1 1-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 1, 8,8,10,12-pentamethyl-4,17-dioxabicycio [14.1.0] heptadecane-5,9-dione and

(1 R, 3S (E), 7S, 10R, 1 1 S, 12S, 16R) -7.1 1-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazoiyl) ethenyl) - 1, 8,8,10,12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione

(4S, 7R, 8S, 9S, 13E, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-oxazolyl) ethenyl) -1-oxa-5, 5,7,9,14-pentamethyl-cyclohexadec-13-ene-2,6-dione (1 S, 3S (E), 7S, 10R, 1 1 S, 12S, 16S) -7.11-dihydroxy-3- (1-methyl-2- (2-methyl-4-oxazoιyi) ethenyi) -1, 3 , 3, 10,12-pentamethyl-4, 17-dιoxabιcycio [14.1.0] heptaαecaπ-5,9-dιon and

(1 R, 3S (E), 7S.10R, 11 S, 12S, 16R) -7,11-dihydroxy-3- {1-methyl-2- (2-methyi-4-oxazol1yl) ethenyl) -1, 8,8,10,12-pentamethyl-4,17-dioxabιcyclo [14.1.0] heptadecane-5,9-dione

(4S, 7R, 8S, 9S, 13E, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-oxa- 5,5,7, 9, 14-pentamethyl-cyclohexadec-13-en-2,6-dione

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

(4S, 7R, 8S, 9S, 13E, 16S (E)) - 4,8-dihydroxy-7-ethyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1- oxa-5,5,9,14-tetramethyi-cyclohexadec-13-ene-2,6-dione

(1 S, 3S (E), 7S, 10R, 11 S, 12S, 16S) -7, 11 -dihydroxy-10-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl ) -1, 8,8, 12-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and (1 R, 3S (E), 7S, 10R, 11 S, 12S, 16R) -7, 11-Dihydroxy-10-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1, 8,8,12-tetramethyl-4,17-dioxabicyclo [14.1. 0] heptadecane-5,9-dione

(4S, 7R, 8S, 9S, 13E, 16S (E)) - 4,8-Dihydroxy-14-ethyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1 - oxa-5,5,7,9-tetramethyl-cyclohexadec-13-ene-2,6-dione

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

(4S, 7R, 8S, 9S, 13E, 16S (E)) - 4,8-dihydroxy-14-proyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1- oxa-5,5,7,9-tetramethyl-cyciohexadec-13-en-2,6-dione

(1S, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-1-propyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 8,8,10,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and (1 R, 3S (E), 7S, 10R, 11 S, 12S, 16R) -7,11-dihydroxy-1-propyi-16- (1-methyi-2- (2-methyl-4-thiazoiyl) ethenyl ) -8,8.10,12-tetramethyi-4.17-dioxadicycio [14.1.0] heptadecane-5,9-dione

(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-16- {1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5,7,9,13, 14-hexamethyl-cyclohexactec-13-en-2,6-dione

(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyi) ethenyl) -1, 8, 8,10,12,16-hexamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and (1R, 3S (E), 7S, 10R, 11S, 12S, 16S) -7.11 -Dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazoiyl) ethenyl) -1,8,8,10,12,126-hexamethyl-4,17-dioxabicyclo [14.1.0] heptadecane 5.9- dione

(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-oxa- 5,5,7, 9,13, 14-hexamethyl-cyclohexadec-13-ene-2,6-dione

(1S, 3S (E), 7S, 10R, 11 S, 12S, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-pyridyl) ethenyl) -1,8,8,10 , 12,16-hexamethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and (1R, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy- 3- (1-methyl-2- (pyridyl) ethenyi) - 1, 8,8,10,12,16-hexamethyi-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione

Representation of partial fragments A (WO 99/07692)

The partial fragments (synthesis building blocks) of the general formula A can easily be obtained from a) a pantolactone of the general formula Ila

wherein

Rla ' _t Rlb' each represent a methyl group or b) a malonic acid dialkyl ester of the general formula XXVII

XXVIII

Alkyl Q ₂ C y C0 ₂ alkyl

wherein

Rla ^ Rl b 'j _e j _{n of} the general formula A have the meaning given, and

Alkyl independently of one another a C- | -C20-alkyl-, C3-C-) o-cycloalkyl- or C4-C20-

Alkyicycloalkylrest mean.

manufacture as a starting product.

The partial fragments A, in which R ^{1 a} '= R ^{1 b} ' = methyl, can be produced from inexpensive pantolactone in an efficient manner with an optical purity> 98% ee.

The synthesis is described in the following scheme 1 using the example of D - (-) - pantolactone. The corresponding compounds ent-A-II to ent-A-XIV, which are enantiomeric to A-II to A-XIV, are obtained from L - (+) - pantolactone and the corresponding racemic compounds rac-A-II to from racemic DL-pantolactone rac-A-XIV:

Scheme 1

_R 1 a _R 1 b 'c OH

A-Il A-Il! A-IV A-V

A-Vl

A-Xll A-Xl II A-XIV

^* : only if R ^2a 'or R ^2b ' in A-Xl II is hydrogen

Step a (A-Il = A-Ill):

The free hydroxyl group of pantolactone (A-II) is protected by the methods known to those skilled in the art. As protective group PG ^ come 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, tribenzylsilyl, tribenzylsilyl -, Benzyi, para-nitrobenzyl, para-methoxybenzyl, formyl, acetyl, 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). Preference is given to protective groups which can be cleaved under acidic reaction conditions, such as, for example, 3. the methoxymethyl, tetrahydropyranyi, tetrahydrofuranyi, trimethylsilyl radical. The tetrahydropyranyl radical is particularly preferred.

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

The protected lactone A-Ill is reduced to lactol A-IV. Reactivity modified aluminum hydrides such as e.g. Diisobutyl aluminum hydride. The reaction takes place in an inert solvent such as e.g. Toluene, preferably at low temperatures.

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

Lactol A-IV is opened with the addition of one carbon atom to the hydroxyolefin A-V.

The methods known to the person skilled in the art such as e.g. the Tefbe olefination, the Wittig or Wittig / Homer reaction, the addition of an organometallic compound with elimination of water. The is preferred

Wittig reaction using methylitriarylphosphonium halides such as e.g.

Methyl triphenylphosphonium bromide with strong bases such as e.g. n-butyl lithium, potassium tert-butanoate, sodium ethanolate, sodium hexamethyldisiiazane; n-butyllithium is preferred as the base.

Step d (A-V => A-VI):

The free hydroxyl group in AV is protected by methods known to those skilled in the art. The protective groups PG ⁹ are the protective groups known to the person skilled in the art, as already mentioned above for PG ⁸ in step a (A-II => A-III).

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 residue.

Step e (A-VI = A-VII):

Anti-Markovnikov water is added to the double bond in A-VI. The processes known to the person skilled in the art are suitable for this purpose, for example the reaction with boranes, their subsequent oxidation to the corresponding boric acid esters and their saponification. Preferred boranes are, for example, the borane-tetrahydrofuran complex, the borane-dimethyl sulfide complex, 9-borabicyclo [3.3.1] nonane in an inert solvent such as, for example, tetrahydrofuran or diethyl ether. As an oxidizing agent preferably hydrogen peroxide, preferably alkali metal hydroxides such as sodium hydroxide for the saponification of the boresters

Step f (A-VI = »A-VII): The protective group PG ⁸ introduced under step a) is now cleaved according to the processes known to the person skilled in the art. If it is an acidic cleavable protective group, then dilute mineral acids in aqueous alcoholic solutions are suitable, the use of catalytic amounts of acids such as para-toluenesulfonic acid, para-toluenesulfonic acid pyridinium salt, camphorsulfonic acid in alcoholic solutions, preferably in ethanol or Isopropanol.

Step g (A-VII => A-IX):

A joint protection of both alcohol functions of the mono-protected 1 .3-diol in A-

VII is by direct ketalization with a carbonyl compound of the general formula R ¹ 6 ^a -CO-R ^{1 6b} , or by transketalization with a ketal of the general formulas, Rl6a_c (0C ₂ H5) ₂ -R ^{1 6b} , R ^{1 6a} -C ( OC ₂ H ₄ ) ₂ -R ^{1 6b} , Rl 6a.C (OCH ₂ C (CH3) 2CH2θ) -R ¹ 6 ^b wherein each R ^ a _unc j Rl 6b have the meanings given above, possible under acid catalysis. Suitable acids are the acids already mentioned under step f), preference is given to the use of para-toluenesulfonic acid, optionally with the addition of copper (II) or cobalt (II) salts such as copper (II) sulfate.

Step h (A-VIM => A-IX):

Protection of both alcohol functions of the 1,3-diol in A-VIII is possible by direct ketalization with a carbonyl compound of the general formula Rl ^6a _co-Rl 6 ^b , or by transketalization with a ketal of the general formulas, R ¹ 6a_c (0C2H5) 2-R ¹ ^ ^b , Rl6a_c (0C ₂ H ₄ ) 2-R ^{1 6b} , R ^{1 6a} -C (OCH ₂ C (CH3) 2CH ₂ O) -R ^{1 6b} wherein R ^ ^a and Rl6b each have the meanings given above, below Acid catalysis possible. Transketalization with 2,2-dimethoxypropane is preferred. Suitable acids are the acids already mentioned under step f); preference is given to using camphorsulfonic acid.

Step i (A-IX = * A-X):

The protective group PG introduced under step d) is then split using the methods known to the person skilled in the art. If it is a silyl ether, the reaction with fluorides such as tetrabutylammonium fluoride, the hydrogen fluoride-pyridine complex, potassium fluoride or the use of dilute mineral acids, the use of catalytic amounts of acids such as para-toluenesulfonic acid, para-toloisoisifonic acid is suitable for the cleavage -pyndinium salt, Campner sulfonic acid in alcoholic solutions, preferably in ethanol or isopropanol.

Step k (A-X = A-Xl): The oxidation of the primary alcohol in A-X to the aldehyde takes place according to the methods known to the person skilled in the art. Examples include oxidation with 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 I (A-Xl => A-Xl I):

The conversion of the aldehydes A-Xl to alcohols of the formula A-Xll takes place with organometallic compounds of the general formula M-CHR ^a 'R ² ', in which M is an alkali metal, preferably lithium or a divalent metal MX, in which X represents a halogen and the radicals R ^2a 'and R ^2b ' each have the meanings given above. Magnesium and zinc are preferred as divalent metal, and chlorine, bromine and iodine are preferred as halogen X.

Step m (A-Xll => A-Xlll):

The oxidation of the secondary alcohol in A-Xll A-Xlll takes place according to the conditions mentioned under step k). Oxidation with N-methylmorpholino-N-oxide using tetrapropylammonium perruthenate is preferred.

Step n (A-Xlll => A-XIV):

In the event that R ^2a 'in A-Xlll is hydrogen, there is the possibility of introducing a second radical R ^2a ', which has the meanings mentioned above, except hydrogen. For this purpose, using strong bases such as lithium diisopropylamide, the ketone in A-XIII is converted into the enolate and reacted with a compound of the general formula XR ^2a ', where X represents a halogen. Halogen X is preferably chlorine, bromine and iodine.

The previously described route can also be used to synthesize C1-C6 epothilone building blocks which contain a carboxylic acid or its ester at C-1

The synthesis of the building block A-XXII is described in the following scheme 2 using the example of the intermediate AV derived from D - (-) - pantolactone. The corresponding compounds ent-AV to ent-A-XXVII which are enantiomeric to AV to A-XXVII are obtained from L - (+) - pantolactone and the corresponding racemic compounds rac-AV to rac-A-XXVII from racemic DL-pantolactone:

Scheme 2

A-XV A-XVI A-XVI I

_R 1 a _R 1b ' _R 2a' _{Rl a} . _R ι "p 2a '

PG ¹⁰ O OPG ³ OH PG ¹⁰ O OPG ³ O

A-XVI II A-XIX A-XX

A-Vll X

A-XXI II A-XXI V A-XXV

A-XXVI A-XXVII Step o (AV => A-XV):

The oxidation of the primary alcohol in A-V to the aldehyde A-XV takes place according to, below

Step k) conditions mentioned. The oxidation method according to Swern is preferred.

Step p (A-XV => A-XVI):

The reaction of the aldehydes A-XV to alcohols of the formula A-XVI takes place with organometallic compounds of the general formula M-CHR ^2a 'R ^2b ', in which M is an alkali metal, preferably lithium or a divalent metal MX, in which X represents a halogen and the radicals R ^2a 'and R ^2b ' each have the meanings given above. Magnesium and zinc are preferred as divalent metal, and chlorine, bromine and iodine are preferred as halogen X.

Step q (A-XVI => A-XVI I):

Anti-Markovnikov water is added to the double bond in A-XVI. The methods described under e) are suitable for this.

Step r (A-XVI l => A-XVI II):

The free hydroxyl group in A-XVI I is protected by the methods known to those skilled in the art. The protective groups PG ¹ ^ are the protective groups known to the person skilled in the art, as already mentioned above for PG ⁸ in step a (A-II => A-III).

Protective groups which are preferred are those which are basic or hydrogenolytic

Reaction conditions can be split, e.g. Benzyi, para-nitrobenzyl,

Acetyl, propionyl, butyryl, benzoyl radical. The benzoyl radical is particularly preferred.

Step s (A-XVIII => A-XIX):

The oxidation of the secondary alcohol in A-XVII to the ketone A-XIX takes place according to the conditions mentioned under step k). Oxidation with N-methylmorpholino-N-oxide using tetrapropylammonium perruthenate is preferred.

Step t (A-XIX => A-XX):

The protection group PG ¹⁰ in XIX is now split selectively. If it is a hydrogenolytically cleavable protective group, hydrogenation is preferably carried out in the presence of palladium or platinum catalysts in inert solvents such as, for example, ethyl acetate or ethanol. If it is a basic cleavable protective group, use is preferably made of saponification with carbonates in alcoholic solution, such as, for example, potassium carbonate in methanol, and saponification with aqueous solutions of alkali metal hydroxides, such as, for example, lithium hydroxide or sodium hydroxide Use of organic, water-miscible solvents such as methanol. Ethanol, tetranydrofuran or dioxane.

Step u (A-XVI I => A-XXI): The oxidation of the alcohols in A-XVII to the ketoaldehyde A-XXI takes place according to the conditions mentioned under step k). Oxidation with N-methylmorpholino-N-oxide using tetrapropylammonium perruthenate and the Swern method are preferred.

Step v (A-XX => A-XXI):

The oxidation of the primary alcohol in A-XX to ketoaldehyde A-XXI takes place according to the conditions mentioned under step k). Oxidation with N-methylmorphoiino-N-oxide using tetrapropylammonium perruthenate is preferred.

Step w (A-XXI => A-XXII):

The oxidation of the aldehyde in A-XXI to the carboxylic acid A-XXII (R ^{1 b} = hydrogen) takes place according to the methods known to the person skilled in the art. Examples include oxidation according to Jones, oxidation with potassium permanganate, for example in an aqueous system composed of tert-butanol and sodium dihydrogen phosphate, oxidation with sodium chlorite in aqueous tert-butanol, if appropriate in the presence of a chlorine scavenger such as 2-methyl-2-butene.

The oxidation of the aldehyde in A-XXI to the ester A-XXII, in which R ¹⁴ b has the meanings given above and is not hydrogen, can be carried out, for example, with pyridinium dichromate and the desired alcohol HO-R ^14b in an inert solvent such as dimethylformamide.

Step x (A-Vll => A-XXIII):

The oxidation of the primary alcohol in A-VIII to the aldehyde A-XXIII takes place according to the conditions mentioned under step k). Oxidation with N-methylmorpholino-N-oxide using tetrapropylammonium perruthenate and the Swern method are preferred.

Step y (A-XXIII => A-XXIV):

The oxidation of the aldehyde A-XXIII to the carboxylic acid or its ester A-XXIV takes place according to the conditions already described under w).

Step z (A-XXIV => A-XXV):

The protection group PG§ introduced under step d) is split as described under step i Step aa i _. A-XXV => A-XXVI):

The oxidation of the primary alcohol in A-XXV to the aldehyde A-XXVI takes place according to the conditions mentioned under step k). Oxidation with N-methylmorpholino-N-oxide using tetrapropylammonium perruthenate is preferred, as is the Swern method.

Step from (A-XXVI = x> A-XXVII):

The conversion of the aldehydes A-XXVI to alcohols of the formula A-XXVII takes place according to the conditions mentioned under step I).

Step ac (A-XXVII => A-XXII):

The oxidation of the secondary alcohol in A-XXVII to the ketone A-XXII takes place according to the conditions mentioned under step k). Oxidation with N-methylmorpholino-N-oxide using tetrapropylammonium perruthenate is preferred.

The compounds of the formula A, in which R ^{1 a} ' _and d Rlb' can all have the meanings given in the general formula A, can also be prepared efficiently and with high optical purity from cheap or easily accessible malonic acid dialkyl esters.

The synthesis is described in Scheme 3 below:

Scheme 3

Alkyl- ^>

A-XXVIII A-XXIX A-XXX

A-XXXI A-XXXI 1 A-XXXI II

aι

A-VIII or ent-A-VIII

Step ad (A-XXVIII => A-XXIX): Correspondingly substituted malonic acid ester derivatives A-XXVIII, which are either commercially available or can be prepared from malonic acids or their alkyl esters by methods known to the person skilled in the art, are reduced to diols A-XXIX. The reducing agents known to the person skilled in the art, e.g. Diisobutyl aluminum hydride, complex metal hydrides such as e.g. Lithium aluminum hydride.

Step ae (A-XXIX => A-XXX):

A free hydroxyl group in A-XXIX is selectively protected by methods known to those skilled in the art. The protective groups PG ^{1 1 which} are known to the person skilled in the art, as already mentioned above for PG ^ in step a (A-II => A-III), are suitable.

Protective groups containing silicon are preferred.

Step af (A-XXX = A-XXXI):

The oxidation of the remaining primary hydroxyl group in A-XXX to the aldehyde A-XXXI takes place according to the conditions mentioned under step k). Oxidation with is preferred

N-methyl-morpholino-N-oxide using tetrapropyammonium per-ruthenate, the use of Pyπdiniumchlorochromat. Pyπαiniumdichromat and the Swern method.

Step ag (A-XXXI => A-XXXI I): The aldehydes A-XXXI are reacted with an ester of acetic acid chG ¹ OC (0) CH3, in which chG ^{1 is} a chiral auxiliary group, in the sense of an aldol reaction. The compounds chG ¹ OC (0) CH3 are used in optically pure form in the aldol reaction. The type of chiraic auxiliary group determines whether the aldol reaction proceeds with high diastereoselectivity or results in a diastereomer mixture that can be separated by physical methods. An overview of comparable diastereoselective aldol reactions can be found in Angew. Chem. 99 (1987), 24-37. As chiraie auxiliary groups chG ^ -OH, for example, optically pure 2-phenyi-cyclohexanol, pulegol, 2-hydroxy-1, 2,2-triphenylethanol, 8-phenylmenthol are suitable.

Step ah (A-XXXII => A-XXXI II):

The diastereomerically pure compounds A-XXXII can then be converted into enantiomerically pure compounds of the type A-XXXIII or ent-A-XXXIII by saponification of the ester unit with simultaneous release of the reusable chiral auxiliary component chG ¹ -OH by processes known to the person skilled in the art. Suitable for saponification are carbonates in alcoholic solution such as, for example, potassium carbonate in methanol, aqueous solutions of alkali hydroxides such as, for example, lithium hydroxide or sodium hydroxide using organic, water-miscible solvents such as, for example, methanol, ethanol, tetrahydrofuran or dioxane.

Step ai (A-XXXII => A-Vlll):

As an alternative to step ah, the chiraie auxiliary group can also be removed reductively. In this way, the enantiomerically pure compounds of the type A-VIII or ent-A-VIII are obtained. The reduction can be carried out according to the methods known to the person skilled in the art. As reducing agents are e.g. Diisobutyl aluminum hydride and complex metal hydrides such as e.g. Lithiumiumiumiumhydrid in question.

The compounds A-VIII or ent-A-VIII can, as described above, be converted into compounds of the type A-Xlll or ent-A-XIII. Correspondingly, compounds of type A-XXXIII or ent-A-XXXIII can be converted into compounds of type A-XXII or ent-A-XXH according to the methods described above.

As an alternative to the route described above, the sequence can also be carried out without using a chiral auxiliary group chG ^' '. In this way, racemic mixtures of compounds of the type rac-A-III or rac-A-XXXHI are then receive the corresponding racemic precursors. These mixtures can in turn be separated according to the methods known to those skilled in the art for resolving racemates, for example chromatography on chiral columns. The synthesis can also be continued with the racemic mixtures.

Representation of partial fragments B (see also WO 99/07692)

Scheme 4

_R 4a ' _R 4b'

, 4a 'o 4b'

-> AlkytO

OPG ¹² HO -> PG ¹³ 0

OPG 2 OPG ¹ 2

B-VIII B-IX B-X

Step a (B-Il ^ B-Ill):

A hydroxyl group in B-II is protected by the methods known to the person skilled in the art. The protective groups PG ¹² are the protective groups known to the person skilled in the art, as already mentioned above for PG ⁸ in step a (A-il => A-III).

Protective groups containing silicon, which can be cleaved under acidic reaction conditions or using fluoride, such as, for example, the trimethylsilyl, Tπethylsilyl- tert -Butyldimethylsilyl- tert -Butyldiphenvisilyl- Tπbenzylsilyl-

Tπisopropylsilyi residue.

The tert-butyldimethylsilyi radical is particularly preferred

Step b (B-Ill ^ B-IV)

The free hydroxyl group in B-III is converted into a leaving group LG by the methods known to the person skilled in the art. Halogens such as e.g. Bromine or iodine or alkyl or aryl sulfonates which are prepared from the corresponding sulfonic acid halides or sulfonic acid anhydrides by the methods known to the person skilled in the art.

Trifluoromethane suifonate is preferred as the leaving group LG.

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

The compound B-IV is alkylated with the enolate of a carbonyl compound of the general formula BV, in which chG ^{2 can be} a simple alkoxy group or a chiral auxiliary group, by the methods known to the person skilled in the art. The enolate is produced by the action of strong bases such as lithium diisopropylamide, lithium hexamethyidisilazane at low temperatures. The chiraie auxiliary group chG ² -H (B-VI) are chiraie, optically pure and inexpensive alcohols such as pulegol, 2-phenylcyclohexanol, 2-hydroxy-1, 2,2-tπphenylethanol, 8-phenylmenthol or optically pure and inexpensive, reactive NH-containing compounds such as nurse, amino acids, lactams or oxazolidinones. Oxazolidinones are preferred, particularly preferably the compounds of the formulas B-Vla to B-Vld. The choice of the respective antipode determines the absolute stereochemistry of the α-carbonyl carbonate of the compound of the general formula B-VIII. In this way, the compounds of the general formulas B-VIII to B-XVII or their respective enantiomers ent-B-VII to ent-B-XVII can be obtained in an eπantiomerically pure manner. If an achira alcohol such as ethanol is used as chG ² -H (B-VI), the racemic compounds rac-B-VII to rac-B-XVII are obtained.

Step d (B-Vll => B-Vl II)

If the group chG ^{2 represents} one of the chiral auxiliary groups mentioned under step c, this is recovered by transesterification of B-VIII into an alkyl ester of the general formula B-VIII. The transesterification takes place according to the methods known to the person skilled in the art. Transesterification with simple alcohols such as methanol or ethanol in the presence of corresponding titanium (IV) alcoholates is preferred Step e (B-VMI => B-IX)

The ester in 3-VIII is αα converted to the Alkonol 3-iX. Suitable reducing agents are the reducing agents known to the person skilled in the art, such as aluminum hydrides such as lithium aluminum hydride or diisobutyl aluminum hydride. The reaction takes place in an inert solvent such as e.g. Diethyl ether, tetrahydrofuran, toluene.

Step e (B-Vll => B-IX):

As an alternative to steps d) and e), the carbonyi group in B-VIII can be reduced directly to the alcohols of the general formula B-IX under the conditions mentioned under step e). The chiraie auxiliary component chG ² -H can also be recovered here.

Step f (B-IX => B-X):

In the event that R3 is not a hydrogen atom, the primary hydroxyl group in B-IX is first oxidized to the corresponding aldehyde by methods known to those skilled in the art. Examples include oxidation with pyπdinium chlorochromate, pyπdinium dichromate, chromium oxide-pyπdin complex, oxidation by Swern or related methods, for example using oxalyl chloride in dimethyl sulfoxide, using Dess-Martin penodinane, using nitrogen oxides such as N-methyl morpholino-N-oxide in the presence of suitable catalysts such as tetrapropylammonium perruthenate in inert solvents. Oxidation according to Swern and with N-methyl-morpholino-N-oxide using tetrapropylammonium perruthenate is preferred. The aldehydes thus obtained can then be converted into corresponding alcohols with organometallic compounds of the general formula MR ^, where M is an alkali metal, preferably lithium or a divalent metal MX, where X represents a halogen and the radical R3 has the meanings given above. Magnesium and zinc are preferred as the divalent metal, and halogen X is preferably chlorine, bromine and iodine. The free hydroxyl group of the secondary alcohol thus obtained (R ^ ^ H) or in the case R3 = H the free hydroxyl group in B-IX is protected by the methods known to the person skilled in the art. The protective groups PG ¹ ^ which are known to the person skilled in the art, as already mentioned above for PG ⁸ in step a (A-II = A-III), are suitable. Preference is given to those protecting groups which can be cleaved under acidic reaction conditions, such as, for example, the methoxymethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl radical. The tetrahydropyranyl radical is particularly preferred. Step g (BX => B-Xl)

The protective group PG ^' ' ^2, which has been darkened in step a), is now split according to the process known to a person. If it is a silyl ether, the reaction with fluons such as tetrabutylammonium fluoride, the hydrogen fluoride-pyrin complex, potassium fluoride is suitable for the split or the use of dilute mineral acids, the use of catalytic amounts of acids such as, for example, para-toluenesulfonic acid, para-toluoisulfonic acid pyπdinium salt, camphorsulfonic acid in alcoholic solutions, preferably in ethanol or isopropanol.

Step h (B-Xl = * B-Xll):

In the event that R ^{25 is} not a hydrogen atom, the primary hydroxyl group in B-Xl is first oxidized to the corresponding aldehyde by methods known to those skilled in the art. Examples include oxidation with pyndinium chlorochromate, pyndinium dichromate, chromium oxide-pyridine complex, oxidation according to Swern or related methods, for example using oxalyl chloride in dimethyl sulfoxide, the use of Dess-Martin-Peπodinans, the use of nitrogen oxides such as N-methyl morpholino-N-oxide in the presence of suitable catalysts such as tetrapropylammonium perruthenate in inert solvents. Oxidation according to Swern and with N-methyl-morpholino-N-oxide using tetrapropylammonium perruthenate is preferred.

The aldehydes thus obtained can then be converted into corresponding alcohols with organometallic compounds of the general formula MR ² ^, where M is an alkali metal, preferably lithium or a divalent metal MX, where X represents a halogen and the radical R ² ^ has the meanings given above. Magnesium and zinc are preferred as divalent metal, and chlorine, bromine and iodine are preferred as halogen X.

If appropriate, the free primary hydroxyl group is converted into a halide by the processes known to the person skilled in the art. Preferred halides are chlorine, but especially bromine and iodine. The substitution of the hydroxyl group for a bromine can e.g. by means of triphenylphosphine / tetrabromomethane but also by any other process known to the person skilled in the art. The establishment of an iodine atom can be derived from the bromide by substitution e.g. according to Finkelstein with sodium iodide in acetone. Direct conversion of the hydroxyl group into the iodide is also possible, e.g. using elemental iodine, imidazole and Tπphenylphosphin in dichloromethane.

Step i (B-Xll => B-Xlll):

Should the C13-C16 unit be linked to position 12 of the epothilone residue or epothilone fragments, for example a C7-C12 unit by Wittig reaction, such as For example, described in Nature Vol. 387, 268-272 (1997), the triphenylphosphonium halides (R ^{1 7} = P (Ph) 3 ⁺ Hal ^_ alkyl) are started from the halides B-XII by the processes known to the person skilled in the art - or aryl phosphonates (R ^{1 7} = P (0) (OQ) 2) or phosphine oxides (R ^{1 7} = P (0) Ph2) of the type B-XII. Ph is phenyl; shark stands for F, - -Cl, Br or I and Q is a CjCj o-alkyl or phenyl radical.

For the preparation of the phosphonium salts e.g. the reaction of the corresponding halides with triphenylphosphine in solvents such as toluene or benzene, optionally in the presence of a base such as triethylamine or diisopropylethylamine.

The representation of the phosphonates can e.g. by reaction of the halides B-Xl with a metalated dialkyl phosphite. The metalation is usually done with strong bases such as Butyllithium. The representation of the phosphine oxides can e.g. by reaction of the halides B-Xl with metallized diphenylphosphine and subsequent oxidation. Strong bases such as butyllithium are also suitable for the metalation. The subsequent oxidation to phosphine oxide can then e.g. with dilute aqueous hydrogen peroxide solution.

Alternatively, the compounds of the general formula B-XIII can be prepared via the route described in Scheme 5.

Scheme 5

B-XIV B-XV B-XVI B-XVII

B-XVI I -— "—- B-Xl

Step k (B-XIV = B-XV):

Starting from cheaply available ethyl acetate derivatives of the general formula B-XIV, in which R ^ ^a 'and R ^ b' have the meanings given above, the ester enolate is prepared by the action of strong bases such as lithium diisopropylamide, lithium hexamethyldisilazane at low temperatures and with 3-halogen -1-propyne, preferably 3-bromo-1-propyne, to give compounds of the general formula B-XV. Step I (B-XV = ^ B-XVI):

The ester 3-XV is reduced to the alcohol B-XVI by the methods described in step e), preferably using diisobutylaluminum hydride.

Step m (B-XVI => B-XVII):

In the event that R ^{3 is} not a hydrogen atom, the primary hydroxyl group in B-XVI is first oxidized to the corresponding aldehyde by methods known to those skilled in the art. Examples include oxidation with pyridinium chlorochromate, pyridinium dichromate, chromium trioxide-pyridine complex, oxidation according to Swern or related methods, for example using oxalyl chloride in dimethyl sulfoxide

Use of the Dess-Martin periodinan, the use of nitrogen oxides such as

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 is preferred

Tetrapropylammonium perruthenate.

The aldehydes obtained in this way can then be converted into corresponding alcohols with organometallic compounds of the general formula MR ³ , where M is a

Alkali metal, preferably lithium or a divalent metal MX, in which X represents a halogen and the radical R ^{3 has} the meanings given above. Magnesium and zinc are preferred as the divalent metal, and X is preferred as the halogen

Chlorine, bromine and iodine.

The free hydroxyl group of the secondary alcohol thus obtained (R ³ ≠ H) or for the

Case R ³ = H the free hydroxyl group in B-XVII is protected by the methods known to the person skilled in the art. The protective group PG ¹⁴ includes those known to the person skilled in the art

Protecting groups, as already mentioned above for PG ³ in step a (A-Il => A-Ill), are questionable.

Protective groups containing silicon which can be cleaved under acidic reaction conditions or using fluoride, such as e.g. the trimethylsilyl, triethylsilyl, tert.-butyldimethylsilyl, tert.-butyldiphenylsilyl, tribenzyisilyl,

Triisopropylsilyl residue.

The tert-butyldimethylsilyl radical is particularly preferred.

Step n (B-XVII => B-Xl): The acetylene B-XVII can be deprotonated by the processes known to the person skilled in the art and the acetylide obtained can be reacted with formaldehyde to give an alcohol of the general formula B-XI. Alkyl alkali compounds such as butyl lithium or other strong bases such as alkali hexamethyl disilazanes or lithium diisopropyl amide are suitable for deprotonation. Π-Butyllithium is preferred. In the way described in Scheme 5, the racemic compounds rac-B-XI are obtained first. Optionally, the continuous steps rac-B-XV or rac-B-XVI according to Scheme 6 offer the possibility of chemical resolution and thus also access to the enantiomerically rare compounds B-XVI or ent-B-XVI, provided that R ^ a ^' is not identical to R ⁴ '.

Scheme 6

B-XVa

pvi. _rn * p V \ / |

B-XVIa

Step o (rac-B-XV => B-XVa):

The racemic compound rac-B-XV can be transesterified with a chiral, optically obtainable alcohol chG ³ -OH by the methods known to the person skilled in the art, for example the process mentioned under step d), to give a mixture of the diastereomeric esters B-XVa and with separate simple chromatographic methods. Possible chiral alcohols are, for example, pulegol, 2-phenylcyclohexanol, 2-hydroxy-1,2,2-triphenylethanol, 8-phenylmenthol.

Step p (B-XVa => B-XVI and ent-B-XVI):

The diastereomerically pure esters B-XVa can each be reduced to the alcohols B-XVI or ent-B-XVI by the process described in step e, the auxiliary component chG ³ -OH described in step o being able to be recovered.

Step q (rac-B-XVI => B-XVIa):

The racemic compound rac-B-XVI can be converted to a mixture of the diastereomeric esters B-XVIa with a chiral, optically purely obtainable acid chG ⁴ -C02H, its ester, anhydride or acid halide by the methods known to the person skilled in the art and with simple chromatographic Separate methods. Suitable chiraic acids are, for example, malic acid, tartaric acid or their derivatives. Step r (B-XVIa => B-XVI and ent-B-XVI):

The diastereomerically pure esters B-XVIa can each be reduced to the alcohols B-XVI or ent-B-XVI by the process described under step e, or saponified by the methods known to the person skilled in the art, in which case the auxiliary comp described in step u © nente chG ^ -C02H can be recovered.

Representation of the partial fragments C (see also WO 99/07692):

Partial fragments of formula C can be produced from inexpensive, inexpensive malic acid in an efficient manner with high optical purity (> 99.5% ee).

The synthesis is described in the following scheme 7 using the example of L - (-) - malic acid (Cl). Starting from D (+) - malic acid (ent-Cl), the corresponding enantiomeric compounds (ent-C-II to ent-C-XI) are obtained, and starting from racemic malic acid (rac-Cl), the corresponding racemic compounds (rac-C -ll to rac-C-XI).

Scheme 7

'

C-l C-Il C-l II

Step a (malic acid C-1 => C-II):

L - (-) - Malic acid is produced using a method known from the literature (Liebigs Ann. Chem.

1993, 1273-1278) converted into the hydroxylactone C-II.

Step b (C-Il => C-Ill):

The free hydroxy group in compound C-II is protected by the methods known to the person skilled in the art. As protective group PG ^{1 5} which occur to those skilled known protecting groups such as those already mentioned above for PG ⁸ in step a (A-II ^■ => A-III) in question.

Preference is given to protecting groups which can be cleaved under the action of fluoride but are stable under weakly acidic reaction conditions, such as, for example, the tert-butyldiphenylsilyl, tert-butyldimethylsilyl or triisopropylsilyl radical. The tert-butyldiphenylsilyl and the tert-butyldimethylsilyl radical are particularly preferred.

Step e (C-Ill => C-IV):

The lactone C-III is reduced to lactol C-IV by the methods known to the person skilled in the art. Reactivity modified aluminum hydrides such as e.g. Diisobutyl aluminum hydride. The reaction is carried out in an inert solvent such as e.g. Toluene, preferably at low temperatures (-20 to -100 ° C).

Step d (C-IV => C-V):

The conversion of the lactol C-IV to compounds of the formula CV takes place with organometallic compounds of the general formula MR ⁸ 'in which M is an alkali metal, preferably lithium or a divalent metal MX, in which X represents a halogen and R ⁸ ' has the meanings given above having. Magnesium and zinc are preferred as divalent metals, and chlorine, bromine and iodine are preferred as halogen X.

Step e (C-V => C-VI): The primary hydroxyl group in compound C-V is selectively protected against the secondary hydroxyl group by the methods known to the person skilled in the art.

The protective groups PG ^ ^{8 which} are known to the person skilled in the art, as mentioned above for PG ⁸ in step a (A-II = A-III), are suitable.

Preferred protective groups are those which can be cleaved under weakly acidic reaction conditions, such as e.g. the trimethylsilyl-, triethylsilyl, -tert.-

Butyldimethylsilyl residue.

The tert-butyldimethylsilyl radical is particularly preferred.

Step f (C-Vl => C-Vll): The oxidation of the secondary alcohol in C-Vl to the ketone C-Vll takes place according to the methods known to the person skilled in the art. Examples include oxidation with pyridinium chlorochromate, pyridinium dichromate, chromium trioxide-pyridine complex, oxidation by Swern or related methods, for example using oxalyl chloride in dimethyl sulfoxide, the use of Dess-Martin periodinane, the use of nitrogen oxides such as N-methyl morpholino-N-oxide in the presence of suitable catalysts such as tetrapropylammonium perruthenate in inert solvents. Swern oxidation is preferred. Step g (C-Vll => C-Vlll):

For compounds in which U is CR ^ 'R ^' '', this grouping is established according to the methods known to the person skilled in the art. Methods such as the Wittig or Wittig / Homer reaction, the addition of an organometallic compound MCHR ¹ 'R ² ' with elimination of water are suitable for this. The Wittig and Wittig / Homer reaction is preferred using phosphonium halides of the type CR ^{1 1} 'R ^{1 2} ' P (Ph) 3 ⁺ Ha | - or phosphonates of the type CR ¹ 'R ^{1 2} ' P (0) ( OAlkyl) ₂ with Ph equal to phenyl, R ^{1 1} ', R ¹² ' and halogen in the meanings already mentioned with strong bases such as, for example, n-butyllithium, potassium tert-butanoate, sodium ethanolate, sodium hexamethyidisiiazane; n-butyllithium is preferred as the base.

For compounds in which U represents two alkoxy groups OR ⁹ or a C2-Cιo-alkylene-α, ω-dioxy group, the ketone is by the methods known to the person skilled in the art, for example using an alcohol HÖR ⁹ or a C2-Cιo-alkylene-α , ω- diols ketalisiert under acid catalysis.

Step h (C-VIII => C-IX):

The protective group PG ¹⁸ introduced under e is now selectively cleaved in the presence of PG ¹ ^ using the processes known to those skilled in the art. If the protective group can be split off with acid, the cleavage is preferably carried out under weakly acidic conditions, such as, for example, by reaction with dilute organic acids in inert solvents. Acetic acid is preferred.

Step i (C-IX => C-X):

The oxidation of the primary alcohol in C-IX to the aldehyde of the general formula C-X takes place according to the methods known to the person skilled in the art. Examples include oxidation with 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 k (CX = C-XI): The conversion of the aldehydes CX to alcohols of the general formula C-XI takes place according to the methods known to the person skilled in the art with organometallic compounds of the general formula MR ^ ', where M is an alkali metal, preferably lithium or a divalent metal MX, where X represents a halogen and the rest R ^ 'the above has the meaning mentioned. Magnesium and zinc are preferred as divalent metal, and chlorine, bromine and iodine are preferred as halogen X.

Step I (C-XI => C-XI I):

The alcohol C-XI is oxidized to the ketone of the general formula C-XII by the processes mentioned under k) or by Jones oxidation. Oxidation according to Jones is preferred.

Representation of the partial fragments ABC and their cyclization to I:

Partial fragments of the general Formei AB

wherein R ³ , R ^4a , R ^4b , R ⁵ , R ⁶ , R ²⁵ , R ⁷ , R ²⁰ , D, E, U and V have the meanings already mentioned, from the fragments B and C described above according to the in Scheme 8 obtained procedure.

Scheme 8

BC

Step a (B + C = BC):

The compound B, in which R ^{1 7 has} the meaning of a Wittigsaize and any additional carbonyl groups that may be present are protected, is deprotonated by a suitable base such as, for example, n-butyllithium, lithium diisopropylamide, potassium tert-butoxide, sodium or lithium hexamethyldisilazide and with a compound C, in which W has the meaning of an oxygen atom. Partial fragments of the general formula ABC

ABC,

where R ^, R ¹ b, R ² a, R2b, _R 3, _R 4 _{a> R} 4b, _R 5, _R 6 _{t R} 25 _{? R} 7 _{> R} 8 _{? R} 14 _R 15, _{D) E>} u and Z have the meanings already mentioned, are obtained from the fragments AB and C described above by the process shown in Scheme 9.

Scheme 9

ABC

Step b (BC + A = ABC): The compound BC, in which V has the meaning of an oxygen atom and any additional carbonyl groups which may be present are protected, is alkylated with the enolate of a carbonyl compound of the general formula A, in which Z has the meaning of an oxygen atom. The enolate is formed by the action of strong bases such as e.g. Lithium diisopropylamide, lithium hexamethyldisilazane produced at low temperatures.

Step c (ABC = I):

The compounds ABC, in which R ^{14 is} a carboxylic acid CO2H and R ^{20 is} a hydrogen atom, are set according to the methods known to the person skilled in the art for the formation of large macrolides to give compounds of the formula I in which Y is of an oxygen atom, in order. The method described in "Reagents for Organic Synthesis, Vol. 16, p 353" is preferred using 2,4,6-trichiorbenzoic acid chloride and suitable bases such as, for example, triethylamine, 4-dimethylaminopyridine and sodium hydride.

Step d (ABC = »I):

The compounds ABC, in which R ^{14 represents} a group CH2OH and R ^{20 represents} a hydrogen atom, can preferably be converted into compounds of the formula I, in which Y has the meaning of two hydrogen atoms, using triphenylphosphine and azodiesters such as, for example, diethyl azodicarboxylate.

The compounds ABC, in which R ^{14 represents} a group CH2θSθ2alkyl or CH2θSθ2Aryl or CH2θSθ2Aralkyl and R ^{20 represents} a hydrogen atom, can be deprotonated with suitable bases such as sodium hydride, n-butyllithium, 4-dimethylaminopyridine, Hünig base, alkylhexamethyldisilazanes to give the compounds of the compounds I, in which Y has the meaning of two hydrogen atoms, cyclize.

The invention also relates to this process for the preparation of the compounds of the general formula I and the new intermediates of the general formulas B, C, BC and ABC including all stereoisomers of these compounds and also mixtures thereof.

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 10:

Scheme 10

A-B-C c or d

A + B A-B + C

C-A-B c or d

A + C C-A + B

c or d

C-B-A

B + C C-B + A

c 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 ketaiization, enol ether formation or reduction.

The invention also relates to these processes for the preparation of the epothilone derivatives of the general formula.

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, BMM, 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, carbopiatin,

=> intercalating substances e.g. from the class of anthracyclines such as

Doxo bicin or from the class of antrapyrazoles such as 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 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 Lometfexol, 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 e.g. Erbstatin, Genistein, Staurosporin, llmofosin, 8-CI-cAMP,

Anti-hormones from the class of anti-progestogens 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, => Compounds inhibiting metastases, for example from the class of eicosanoids such as PGι'2, PGE-j, o-Cxo-PGE-] and their stable derivatives (for example iloprost, cicaprost, misoprostol). = Inhibitors of oncogenic RAS proteins which influence the mitotic signal transduction, such as, for example, inhibitors of farnesyl protein transferase,

Natural or artificially produced antibodies which are directed against factors or their receptors which promote tumor growth, such as, for example, the erbB2 antibody, the invention also relates to medicaments 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 enteric, percutaneous, parenteral or local application according to known galenical methods. They can be administered in the form of tablets, coated tablets, 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.

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

example 1

(4S, 7R, 8S, 9S, 13 (E), 16S (E)) - 4,3-dihydroxy-16- (1-methyl-2- (2-methyl-4-thiazoiyl) ethenyl) -1-oxa -5,5,7,9,14-pentamethyl-cyclohexadec-13-ene-2,6-dione

Example 1 a

(3S) -1-Oxa-2-oxo-3- (tetrahydropyran-2 (RS) -yloxy) -4,4-dimethyl-cyclopentane

The solution of 74.1 g (569 mmol) of D - (-) - pantolactone in 11 anhydrous dichloromethane is mixed with 102 ml of 3,4-dihydro-2H-pyran, 2 g of p-toluenesulfonic acid pyridinium salt under an atmosphere of dry argon and stirred for 16 hours at 23 ° C. It is poured into a saturated sodium bicarbonate solution, the organic phase is separated off and dried over sodium sulfate. After filtration and removal of solvent, the residue is chromatographed on about 5 kg of fine silica gel with a mixture of n-hexane and ethyl acetate. 1 19.6 g (558 mmol, 98%) of the title compound are isolated as a colorless oil. 1 H NMR (CDCI3): δ = 1.13 (3H), 1.22 (3H), 1.46-1, 91 (6H), 3.50-3.61 (1H), 3.86 (1H), 3.92 (1H), 4.01 (1H), 4.16 (1H), 5.16 (1H) ppm.

Example 1 b

(2RS, 3S) -1-Oxa-2-hydroxy-3- (tetrahydropyran-2 (RS) -yioxy) -4,4-dimethyl-cyciopentane

The solution of 1 17.5 g (548 mmol) of the compound shown in Example 1 a in 2.4 I of anhydrous toluene is cooled to -70 ° C. under an atmosphere of dry argon, and 540 ml of a 1, 2 molar solution of diisobutylaluminium hydride in toluene and stirred for 3 hours at -70 ° C. The mixture is allowed to warm to −20 ° C., saturated ammonium chloride solution, water are added and the precipitated aluminum salts are separated off by filtration through Celite. The filtrate is washed with water and saturated sodium chloride solution and dried over magnesium sulfate. After filtration and removal of solvent, 11.4 g (515 mmol, 94%) of the title compound are isolated as a colorless oil, which is reacted further without purification. IR (CHCI3): 3480, 3013, 2950, 2874, 1262, 1 133, 1074, 1026 and 808 cm " ¹ .

Example 1c

(3S) -2,2-dimethyl-3- (tetrahydropyran-2 (R) -yloxy) -pent-4-en-1 -ol and (3S) -2,2-

Dimethyl-3- (tetrahydropyran-2 (S) -yloxy) -pent-4-en-1 -ol The slurry of 295 g of methyl triphenylphosphonium bromide in 2.5 l of anhydrous tetrahydrofuran is added under an atmosphere of dry Argon at -60 ° C with 313 ml of a 2.4 molar solution of n-butyllithium in n-hexane, allowed to warm to 23 ° C, stirred for an hour and cooled to 0 ° C. A solution of 66.2 g (306 mmol) of the compound shown in Example 1b in 250 ml is added Tetra h yd rofu ran. Allow to warm to 23 ° C. and stir for 18 hours. Pour into a saturated sodium bicarbonate solution, extract several times with dichloromethane and dry the combined organic extracts over sodium sulfate. After filtration and removal of the solvent, the residue is chromatographed on about 5 l of fine gravel hedgehog using a gradient system composed of n- Hexane and ethyl acetate. 36.5 g (170 mmol, 56%) of the non-polar, 14.4 g (67.3 mmol, 22%) of the polar THP isomer of the title compound and 7.2 g (33.3 mmol; 1 l are isolated %) of the starting material as a colorless oil. 1 H-NMR (CDCI3), non-polar isomer: δ = 0.78 (3H), 0.92 (3H), 1, 41-1, 58 (4H), 1, 63-1, 87 (2H), 3 , 18 (1H), 3.41 (1H), 3.48 (1H), 3.68 (1H), 3.94 (1H), 4.00 (1H), 4.43 (1H), 5.19 (1H), 5.27 (1H), 5.75 (1H) ppm.

¹ H-NMR (CDCI3), polar isomer: δ = 0.83 (3H), 0.93 (3H), 1, 42-1, 87 (6H), 2.76 (1 H), 3.30 ( 1 H), 3.45 (1 H), 3.58 (1 H), 3.83 (1 H), 3.89 (1 H), 4.65 (1 H), 5.12-5, 27 (2H), 5.92 (1H ppm.

Example 1 d

(3S) -1 - (tert-ButyldiphenyisiIyloxy) -2,2-dimethyl-pentan-3- (tetrahydropyran-2-yloxy) - pent-4-ene

The solution of 59.3 g (277 mmol) of the THP isomer mixture shown in Example 1 c in 1000 ml of anhydrous dimethylformamide is admixed with 28 g of imidazole, 85 ml of tert-butyldiphenylchloride, under an atmosphere of dry argon, and stirred for 16 hours at 23 ° C. It is poured into water, extracted several times with dichloromethane, 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. 106.7 g (236 mmol, 85%) of the title compound are isolated as a colorless oil.

¹ H-NMR (CDCI3): δ = 0.89 (3H), 0.99 (3H), 1.08 (9H), 1.34-1, 82 (6H), 3.40 (1 H), 3.51 (2H), 3.76 (1H), 4.02 (1H), 4.67 (1H), 5.18 (1H), 5.23 (1H), 5.68 (1H), 7.30-7.48 (6H), 7.60-7.73 (4H) ppm.

Example 1 e

(3S) -1 - (tert-butyldiphenylsilyloxy) -2,2-dimethyl-3- (tetrahydropyran-2-yloxy) pentane

5-ol The solution of 3.09 g (6.83 mmol) of the compound shown in Example 1 d in 82 ml of tetrahydrofuran is mixed with 13.1 ml of a 1 molar solution of under an atmosphere of dry argon at 23 ° C. Borane in tetrahydrofuran and allowed to react for 1 hour. 16.4 ml of a 5% strength sodium hydroxide solution and 8.2 ml of a 30% strength hydrogen peroxide solution are then added, and the mixture is stirred another 30 minutes. It is poured into water, extracted several times with ethyl acetate, the combined organic extracts are washed with water, saturated sodium chloride solution and dried over magnesium sulfate. The residue obtained after filtration and removal of solvent is purified by chromatography on fine silica gel using a gradient system composed of n-hexane and ethyl acetate. 1.78 g (3.78 mmol, 55%) of the title compound are isolated as a chromatographically separable mixture of the two THP epimers and 0.44 g (1.14 mmol, 17%) of the title compound from Example 6 in each case as a colorless oil. ¹ H-NMR (CDCI ₃ ), non-polar THP isomer: δ = 0.80 (3H), 0.88 (3H), 1, 10 (9H), 1, 18-1, 80 (9H), 3, 27 (1H), 3.39 (1H), 3.48 (1H), 3.64 (1H), 3.83 (1H), 3.90-4.08 (2H), 4th , 49 (1H), 7.31-7.50 (6H), 7.58-7.73 (4H) ppm.

1 H NMR (CDCI3), polar THP isomer: δ = 0.89 (3H), 0.98 (3H), 1, 08 (9H), 1, 36-1, 60 (4H), 1, 62 -1.79 (3H), 1.88 (1H), 2.03 (1H), 3.37 (1H), 3.50 (1H), 3.57 (1H), 3, 62-3.83 (4H), 4.70 (1H), 7.30-7.48 (6H), 7.61-7.73 (4H) ppm.

Example 1f (3S) -1 - (tert-Butyldiphenylsilyloxy) -2,2-dimethyl-3-hydroxy-pent-4-ene

The solution of 106.7 g (236 mmol) of the compound shown in Example 1d in 1.5 I of anhydrous ethanol is mixed under an atmosphere of dry argon with 5.9 g of pyridinium p-toluenesulfonate and heated to 50 ^{α for} 6 hours C. After removal of the solvent, the residue is chromatographed on fine silica gel with a mixture of n-hexane and ethyl acetate. 82.6 g (224 mmol, 95%) of the title compound are isolated as a colorless oil which also contains about 5 g of ethoxytetrahydropyran. ¹ H-NMR (CDCI3) of an analytical sample: δ = 0.89 (6H), 1.08 (9H), 3.45 (1 H), 3.49 (1 H), 3.58 (1 H) , 4.09 (1H), 5.21 (1H), 5.33 (1H), 5.93 (1H), 7.34-7.51 (6H), 7.63-7, 73 (4H) ppm.

Example 1g (3S) -1 - (tert-butyldiphenylsilyloxy) -2,2-dlmethylpentan-3,5-diol

The solution of 570 mg (1.55 mmol) of the compound shown in Example 1f is reacted analogously to Example 1e and, after workup and purification, 410 mg (1.06 mmoi, 68%) of the title compound is isolated as a colorless oil.

1 H-NMR (CDCI3): δ = 0.82 (3H), 0.93 (3H), 1.08 (9H), 1, 56-1, 79 (2H), 3.11 (1H), 3 , 50 (2H), 3.78-3.92 (3H), 4.02 (1H), 7.34-7.51 (6H), 7.61-7.71 (4H) ppm.

Example 1 h 4 (S) - [2-methyl-1 - (tert-butyidiphenylsilyloxy) prop-2-yl] -2,2-dimethyl- [1, 3] dioxane The solution of 100 mg (0.212 mmol) of the compounds shown in Example 1 e in 2.5 ml of anhydrous acetone is mixed with 78.9 mg of copper (II) sulfate, a spatula tip of p-toluenesulfonic acid monohydrate and under an atmosphere of dry argon stirred for 16 hours at 23 ° C. Saturated sodium bicarbonate solution is added, the mixture is extracted several times with diethyl ether, 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 fine silica gel using a gradient system composed of n-hexane and ethyl acetate. 24 mg (56 μmol, 27%) of the title compound are isolated as a colorless oil. 1 H-NMR (CDCI3): δ = 0.83 (3H), 0.89 (3H), 1.07 (9H), 1.30 (1H), 1.36 (3H), 1.44 ( 3H), 1.71 (1H), 3.24 (1H), 3.62 (1H), 3.86 (1H), 3.91-4.03 (2H), 7.31- 7.48 (6H), 7.61-7.74 (4H) ppm.

Variant II 320 mg (0.88 mmol) of the compound shown in Example 1 g are reacted analogously to Example 1 h; variant I and, after workup and purification, 234 mg (0.548 mmol, 62%) of the title compound are isolated. Variant III

The solution of 5.60 g (14.5 mmol) of the compound shown in Example 1 g in 250 ml of anhydrous dichloromethane is mixed with 10 ml of 2,2-dimethoxypropane, 145 mg of camphor-10-sulfonic acid and under an atmosphere of dry argon stir for 6 hours at 23 ° C. Triethylamine is added, the mixture is diluted with ethyl acetate, washed with saturated sodium bicarbonate solution and dried over sodium sulfate. After filtration and removal of solvent, the residue is chromatographed on fine silica gel with a mixture of n-hexane and ethyl acetate. 5.52 g (12.9 mmol, 89%) of the title compound are isolated as a colorless oil.

Example 1 i

(4S) -4- (2-Methyl-1-hydroxy-prop-2-yl) -2,2-dimethyl- [1, 3] dioxane

The solution of 5.6 g (13.1 mmol) of the compound shown in Example 1 h in 75 ml of anhydrous tetrahydrofuran is mixed with 39 ml of a 1 molar solution of tetrabutylammonium fluoride in tetrahydrofuran under an atmosphere of dry argon and heated to 50 for 16 hours ° C. Saturated sodium hydrogen carbonate solution is added, the mixture is extracted several times with ethyl acetate, 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 fine silica gel using a gradient system composed of n-hexane and ethyl acetate. 2.43 g (12.9 mmol, 99%) of the title compound are isolated as a colorless oil. 1 H-NMR (CDCI3): δ = 0.87 (3H), 0.90 (3H), 1.35 (1 H), 1.37 (3H), 1.43 (3H), 1.77 ( 1 H), 2.93 (1 H), 3.36 (1 H), 3.53 (1 H), 3.79 (1 H), 3.87 (1 H), 3.96 (1 H) ) ppm. Example 1 k

(4S) -4- (2-ethyl-1-oxo-prop-2-yl) -2,2-dimethyl- [1, 3] dioxane

The solution of 0.13 ml of oxalyl chloride in 5.7 ml of anhydrous dichloromethane is cooled to -70 ° C. under an atmosphere of dry argon, mixed with 0.21 ml of dimethyl sulfoxide. the solution of 200 mg (1.06 mmol) of the compound shown in Example 1 in 5.7 ml of anhydrous dichloromethane and stirred for 0.5 hours. Then it is mixed with 0.65 ml Tπethylamin, allowed to react for 1 hour at -30 ° C and mixed with n-hexane and saturated sodium bicarbonate solution. The organic phase is separated off, the aqueous phase is extracted several times with n-hexane, the combined organic extracts are washed with water and dried over magnesium sulfate. The residue obtained after filtration and removal of solvent is reacted further without purification.

Example 11

(4S) -4 - ((3RS) -2-Methyl-3-hydroxy-pent-2-yl) -2,2-dimethyi- [1,3] dioxane

The solution of 900 mg (4.83 mmol) of the compound shown in Example 1 k in 14 ml of anhydrous diethyl ether is mixed with 2.42 ml of a 2.4 molar solution of ethyl magnesium bromide in diethyl ether under an atmosphere of dry argon at 0 ° C. Warm to 23 ° C and stir for 16 hours. Saturated ammonium chloride solution is added, the organic phase is separated off and dried over sodium sulfate. The residue obtained after filtration and removal of solvent is purified by chromatography on fine silica gel using a gradient system composed of n-hexane and ethyl acetate. 863 mg (3.99 mmol, 83%) of the chromatographically separable 3R and 3S epimers of the titite compound and 77 mg of the title compound described in Example 1 i are each isolated as a colorless oil.

¹ H-NMR (CDCI3) non-polar isomer: δ = 0.86 (3H), 0.89 (3H), 1, 03 (3H), 1, 25-1, 37 (2H), 1, 37 (3H) , 1.46 (3H), 1.49 (1H), 1.84 (1H), 3.35 (1H), 3.55 (1H), 3.81-4.02 (3H) ppm. ¹ H-NMR (CDCI3) polar isomer: δ = 0.72 (3H), 0.91 (3H), 0.99 (3H), 1, 25-1, 44 (2H), 1, 38 (3H) , 1, 43-1, 60 (1 H), 1, 49 (3H), 1, 76 (1 H), 3.39 (1 H), 3.63 (1 H), 3.79-4, 03 (3H) ppm.

Example 1 m (4S) -4- (2-ethyl-3-oxopent-2-yl) -2,2-dimethyl- [1,3] dioxane The solution of 850 mg (3.93 mmol) of a mixture the compounds shown in Example 11 in 63 ml of anhydrous dichloromethane are mixed with molecular sieve (4A, approx. 80 spheres), 690 mg of N-methylmorpholino-N-oxide, 70 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 with a gradient system of n-hexane and ethyl acetate. 728 mg (3.39 mmol, 36%) of the titanium compound are isolated as a colorless oil. t H-NMR (CDCI3): δ = 1.00 (3H), 1.07 (3H), 1.11 (3H), 1.31 (3H), 1.32 (3H), 1.41 ( 3H), 1.62 (1H), 2.52 (2H), 3.86 (1H), 3.97 (1K>, _^ 4.05 (1H) ppm.

Example 1 n 4-tert-butyldimethylsilyloxy-but-2-yn-1-ol

A solution of 175 g of tert-butyldimethylsilyl chloride in 100 ml of a 1: 1 mixture of hexane and. Is slowly added dropwise at 0 ° C. under nitrogen to a solution of 100 g of 2-butyn-1-ol and 158 g of imidazole in 300 ml of dimethylformamide Dimethylformamide and stirred for 2 hours at 0 ° C and 16 hours at 22 ° C. The reaction mixture is diluted with 2.5 l of ether, washed once with water, once with 5% sulfuric acid, once with water, once with saturated sodium bicarbonate solution and with semi-saturated sodium chloride solution. After drying over sodium sulfate and filtration, the mixture is concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-40% ether, 74.3 g of the title compound are obtained as a colorless oil.

IR (film): 3357, 2929, 2858, 1472, 1362, 1255, 1 132, 1083, 1015, 837, 778 cm -1

Example 1o

(4R, 5S, 2'S) -4-methyl-5-phenyl-3- [1-oxo-2-methyl-6- (tert-butyldimethylsilyloxy) hex-4-in-1-yl] -2-oxazolidinone

1.3 ml of lutidine are added under nitrogen to 21 g of a solution of the silyl ether prepared according to Example 1 n in 125 ml of toluene. The mixture is then cooled to -40 ° C. and 17.7 ml of trifluoromethanesulfonic anhydride are added dropwise at this temperature. Then diluted with 100 ml of hexane and stirred for 10 minutes. This solution is added under nitrogen via a reverse frit to a solution consisting of 17.8 g of hexamethyidisilazane in 140 ml of tetrahydrofuran with 73.5 ml of a 1.6 M solution of butyllithium in hexane at -60 ° C (10 minutes stirring time) and 23.3 g (4R, 5S ) -4-methyl-5-phenyl-3-propionyl-2-oxazolidinone in 62 ml of tetrahydrofuran (30 minutes stirring time). The mixture is left to stir at -60 ° C. for 1 hour, 6 ml of acetic acid in 5 ml of tetrahydrofuran are then added, and the reaction mixture is allowed to warm to 22 ° C. The mixture is poured into 80 ml of water and extracted three times with ether. The combined organic phases are washed twice with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the mixture is concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-20% ether, 16.0 g of the title compound is obtained as a colorless oil. ¹ H-NMR (CDCI3): 0 = 0.10 (6H), 0.90 (9H), 0.92 (3H), 1.28 (3H), 2.47 (1 H), 2.61 (1 H), 3.96 (1 H), 4.26 (2H), 4.78 (1H), 5.68 (1H), 7.31 (1H), 7.3-7.5 (3H) ppm.

Example 1 p (2S) -2-ethyl-6- (tert-butyldimethylsilyk> xy) -4-hexinic acid ethyl ester

9.0 ml of titanium (IV) ethylate are added to a solution of 39.3 g of the alkylation product prepared according to Example 10 in 120 ml of ethanol and the mixture is heated under reflux for 4 hours. The reaction mixture is concentrated in vacuo and the residue is dissolved in 100 ml of ethyl acetate. 3 ml of water are added, the mixture is stirred for 20 minutes, the precipitate is filtered off with suction and washed well with ethyl acetate. The filtrate is concentrated, 200 ml of hexane are added and the precipitate is filtered off. The precipitate is washed well with hexane. The filtrate is concentrated in vacuo and the residue thus obtained is purified by chromatography on silica gel. With hexane / 0-20% ether, 25.4 g of the title compound is obtained as a colorless oil. ¹ H-NMR (CD2CI2): δ = 0.10 (3H), 0.90 (9H), 1.2-1.3 (6H), 2.37 (1 H), 2.54 (1 H), 2.60 (1 H), 4.12 (2H), 4.27 (2H) ppm.

Example 1q (2S) -2-Methyl-6- (tert-butyidimethylsilyioxy) hexanoic acid ethyl ester A solution of 10.5 g of the ester prepared according to Example 1 p in 200 ml of ethyl acetate is mixed with 1 g of 10% palladium-on-carbon and stirred for 3 hours at 22 ° C in a hydrogen atmosphere. The catalyst is then 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. With hexane / 0-10% ether, 9.95 g of the title compound is obtained as a colorless oil.

¹ H-NMR (CD2CI2): δ = 0.01 (6H), 0.84 (9H), 1.07 (3H), 1.18 (3H), 1.2 -1.7 (6H), 2.38 (1 H), 3.57 (2H), 4.05 ( 2H) ppm.

Example 1 r (2S) -2-methyl-6- (tert-butyldimethylsilyloxy) hexan-1-ol

63 ml of a 1.2 M solution of diisobutylaluminum hydride in toluene are added to a solution of 9.94 g of the ester prepared according to Example 1 q in 130 ml of toluene at -40 ° C. under nitrogen and the mixture is stirred for 1 hour at this temperature. Subsequently, 15 ml of isopropanol are carefully added and after 10 minutes 30 ml of water are added, the mixture is allowed to come 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. With hexane / 0-30% ether, 7.9 g of the title compound is obtained as a colorless oil. [α] D -8.1 ° (c = 0.97, CHCI3) ¹ H NMR (CDCI3): δ = 0.07 (3H), 0.89 (9H), 0.91 (3H), 1 .0-1 .7 (7H), 3.48 (2H), 3.52 (2H) ppm.

Example 1 s (2S) -2-Methyl-6- (tert-butyldimethylsilyloxy) -1 - (tetrahydro-2H-pyran-2-yloxy) hexane

To 6.4 g of the alcohol prepared according to Example 1 r in 26 ml of methyl chloride are added at 0 ° C. under argon 3.52 ml of dihydropyran followed by 49 mg of p-toluenesulfonic acid monohydrate. After stirring for 1.5 hours at 0 ° C., 10 ml of saturated sodium bicarbonate solution are added and the mixture is diluted with ether. The organic phase is washed twice with semi-saturated sodium chloride solution and dried over sodium sulfate. After filtration, the mixture is concentrated in vacuo and the residue thus obtained is purified by chromatography on silica gel. With hexane / 0-5% ether, 4.75 g of the title compound is obtained as a colorless oil. ¹ H-NMR (CDCI3): δ = 0.05 (6H), 0.89 (9H), 0.92 (3H), 1.0-1.9 (13H), 3.19 (1 H), 3.50 (1 H), 3.55-3.65 (3H) , 4.87 (1H), 4.57 (1H) ppm.

Example 1t (5S) -5-Methyl-6- (tetrahydro-2H-pyran-2-yloxy) hexan-1-ol

13.5 g of tetrabutylammonium fluoride trihydrate are added to a solution of 4.7 g of the THP ether prepared according to Example 1s in 170 ml of tetrahydrofuran under nitrogen and the mixture is stirred for 3 hours. The reaction mixture is then diluted with 800 ml of ether and washed three times with 20 ml of semi-saturated sodium chloride solution and dried over sodium sulfate. After filtration, the mixture is concentrated in vacuo and the residue thus obtained is purified by chromatography on silica gel. With hexane / 0-50% ethyl acetate, 2.88 g of the title compound is obtained as a colorless oil.

¹ H-NMR (CD2CI2): δ = 0.90 / 0.92 (3H), 1.1-1.9 (13H), 3.18 (1 H), 3.40-3.65 (4H), 3.82 (1 H), 4.53 (1 H) ppm.

Example 1 u (2S) -6-iodo-2-methyl-1 - (tetrahydro-2H-pyran-2-yloxy) hexane

12.9 g of iodine are added to a solution of 13.4 g of triphenylphosphine and 3.47 g of imidazole in 200 ml of methylene chloride. The alcohol prepared according to Example 1t is then added dropwise in 50 ml of methyl chloride at 22 ° C. and the mixture is stirred for 30 minutes. The mixture is then concentrated in vacuo and the residue thus obtained is purified by chromatography on silica gel. With hexane / 5% ether, 10.2 g of the title compound is obtained as a pale yellow oil.

¹ H-NMR (CDCI3): δ = 0.94 / 0.95 (3H), 1.0-1 .9 (13H), 3.1-3.3 (3H), 3.4-3.7 (2H), 3.85 (1 H), 4.57 (1 H ) ppm. Example 1v (5S) -5-Methyl-6- (tetrahydro-2H-pyran-2-yioxy) hex-1-yi-triphenyiphosphonium iodide

A mixture of 10.2 g of the iodide prepared above, 40.9 g of triphenylphosphine and 12.1 g of N-ethyldiisopropylamine are stirred at 80 ° C. for 6 hours. After cooling, it is dissolved in 30 ml of methylene chloride, 500 ml of ether are added, the mixture is stirred for 10 minutes and then decanted. This is repeated four more times. The residue thus obtained is dissolved in anhydrous tetrahydrofuran, mixed with toluene and concentrated in vacuo. 17.1 g of the title compound are obtained as a solid foam. ¹ H-NMR (CDCI3): δ = 0.85 / 0.86 (3H), 1.10 (1 H), 1.7-1.9 (13H), 3.13 (1 H), 3.40-3.55 (2H), 3.64 (1 H), 3.79 (1H), 4.49 (1H), 7.6-7.9 (15H) ppm.

Example 1w (S) -Dihydro-3-hydroxy-2 (3H) -furanon

10 g of L - (-) - malic acid are stirred in 45 ml of trifluoroacetic anhydride for 2 hours at 25 ° C. The mixture is then concentrated in vacuo, 7 ml of methanoi are added to the residue and the mixture is stirred for 12 hours. It is then concentrated in vacuo. The residue obtained is dissolved in 150 ml of absolute tetrahydrofuran. The mixture is cooled to 0 ° C. and 150 ml of borane-tetrahydrofuran complex are added and the mixture is stirred at 0 ° C. for 2.5 hours. Then 150 ml of methanol are added. The mixture is left to stir for one hour at room temperature and then concentrated in vacuo. The crude product obtained is dissolved in 80 ml of toluene. 5 g of Dowex® (activated, acidic) are added and the mixture is boiled under reflux for one hour. The Dowex® is then filtered off and the filtrate is concentrated in vacuo. The crude product obtained (7.61 g) is used in the next stage without purification.

Example 1x (S) -dihydro-3 - [[(1, 1-dimethylethyl) diphenylsilyl] oxy] -2 (3H) -furanone

24 ml of tert-butyldiphenylsilyl chloride are added to a solution of 7.61 g of the substance described in Example 1w and 10 g of imidazole in 100 ml / V, / V-dimethylformamide. The mixture is stirred for two hours at 25 ° C and then poured onto ice-cold saturated sodium bicarbonate solution. It is extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. After column chromatography of the crude product on silica gel with a mixture of hexane / ethyl acetate, 13.4 g of the titanium compound are obtained.

1 H NMR (CDCI3): δ = 7.72 (2H), 7.70 (2H), 7.40-7.50 (6H), 4.30-4.42 (2H), 4.01 ( 1 H), 2.10-2.30 (2H), 1.1, 1 (9H) ppm.

Example 1y (2RS, 3S) -3 - [[(1, 1-dimethylethyl) diphenylsilyl] oxy] tetrahydro-2-furanol

80 ml of a 1 molar solution of diisobutylaluminum hydride in hexane at -78 ° C. are added to a solution of 13.4 g of the substance described in Example 1 x in 150 ml of absolute tetrahydrofuran. The mixture is stirred at -78 ° C for 45 minutes and then quenched with water. It is extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. 13.46 g of the title compound are obtained, which is used in the subsequent step without purification.

Example 1z

(2RS, 3S) -3 - [[(1, 1-dimethylethyl) diphenylsilyl] oxy] -1, 4-pentanediol

A solution of 13.46 g of the substance described in Example 1y in 150 ml of absolute tetrahydrofuran is added dropwise to 20 ml of a 3 molar solution of methylmagnesium chloride in tetrahydrofuran at 0.degree. The mixture is stirred for one hour at 0 ° C and then poured onto saturated aqueous ammonium chloride solution. It is extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. After column chromatography of the crude product on silica gel with a mixture of hexane / ethyl acetate, 11.42 g of the titan compound are obtained. 1 H NMR (CDCI3): δ = 7.65-7.75 (4H), 7.40-7.55 (6H), 5.20 (1H), 4.30 (2H), 3.70 (1H), 1.80 (2H), 1.05 (9H) ppm.

Example 1 aa

(2RS, 3S) -5 - [[Dimethyl (1, 1-dimethylethyl) silyl] oxy] -3 - [[(1, 1-dimethylethyl) diphenylsilyl] oxy] -2-pentanol

4.9 g of tert-butyldimethylsilyl chloride are added to a solution of 11.42 g of the substance described in Example 1z and 3.25 g of 1H-imidazole in 120 ml of Λ /, Λ -dimethylformamide. The mixture is stirred for 2 hours at 25 ° C and then poured onto ice-cold saturated sodium bicarbonate solution. It is extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. After column chromatography of the crude product on silica gel with a mixture of hexane / ethyl acetate, 10.64 g of the title compound are obtained. ¹ H-NMR (CDCI3): δ = 7.60-7.70 (4H), 7.30-7.45 (6H), 3.70-3.80 (2H), 3.40 (1 H) , 3.00 (1H), 1.80 (1H), 1.60 (1H), 1.05-1, 12 (12H), 0.82 (9H), 0.02 (6H) ppm .

Example 1ab

(3S) -5 - [[Dimethyl (1, 1-dimethylethyl) silyl] oxy] -3 - [[(1, 1-dimethylethyl) diphenyisilyl] oxy] -2-pentanone To 7.37 ml of oxaiyl chloride in 80 ml of dichloromethane, 13 ml of dimethyl sulfoxide are added at -78 ° C. The mixture is left to stir for 3 minutes and then 1046 g of the substance described in Example 1 aa are added in 100 ml of dichloromethane. After a further 15 minutes of stirring, 52 ml of triethylamine are added dropwise. Then allowed to warm to 0 ° C. The reaction mixture is then poured onto saturated sodium bicarbonate solution. It is extracted with dichloromethane. washes the organic phase with saturated sodium chloride solution, dries over sodium sulfate and concentrates in vacuo. After column chromatography of the crude product on silica gel with a mixture of hexane / ethyl acetate, 9.3 g of the title compound are obtained. ¹ H NMR (CDCI ₃ ): δ = 7.60-7.70 (4H), 7.32-7.50 (6H), 4.25 (1H), 3.72 (1H), 3rd , 58 (1H), 2.05 (3H), 1.90 (1H), 1.75 (1H), 1.13 (9H), 0.89 (9H), 0.01 (6H) ppm. Example 1 ac

(E, 3S) -1 - [[dimethyl (1, 1-dimethylethyl) silyl] oxy] -3 - [[(1, 1 - dimethylethyl) diphenylsilyl] oxy] -4-methyl-5- (2-methylthiazole- 4-yl) -pent-4-en The solution of 6.82 g of diethyl (2-methylthiazol-4-yl) methanephosphonate in 300 ml of anhydrous tetrahydrofuran is cooled to -5 ° C. under an atmosphere of dry argon, mixed with 16. 2 ml of a 1.6 molar solution of n-3uthy! Lithium in n-hexane, allowed to warm to 23 ° C. and stirred for 2 hours. The mixture is then cooled to -78 ° C., the solution of 6.44 g (13.68 mmol) of the compound shown in Example 1 from 150 ml of tetrahydrofuran is added dropwise, the mixture is heated to 23 ° C. and stirred for 16 hours. It is poured into saturated ammonium chloride solution, extracted several times with ethyl acetate, the combined organic extracts 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 fine silica gel using a gradient system composed of n-hexane and ethyl acetate. 6.46 g (11.4 mmol, 83%) of the titanium compound are isolated as a colorless oil.

1 H-NMR (CDCI3): δ = -0.04 (6H), 0.83 (9H), 1, 10 (9H), 1, 79 (1 H), 1, 90 (1 H), 1, 97 (3H), 2.51 (3H), 3.51 (2H), 4.38 (1H), 6.22 (1H), 6.74 (1H), 7.23-7.47 (6H), 7.63 (2H), 7.70 (2H) ppm.

Example l ad

(E, 3S) -3 - [[(1, 1-dimethylethyl) diphenylsilyl] oxy] -4-methyl-5- (2-methylthiazol-4-yl) pent-4-en-1-ol

The solution of 4.79 g (8.46 mmol) of the compound shown in Example 1 ac in 48 ml of tetrahydrofuran is mixed with 48 ml of a 65:35:10 mixture of glacial acetic acid / water tetrahydrofuran and stirred for 2.5 days 23 ° C. It is poured into saturated sodium carbonate solution, extracted several times with ethyl acetate, the combined organic extracts are washed with saturated sodium chloride solution and dried over sodium sulfate. Purifies the residue obtained after filtration and removal of solvent by chromatography on fine silica gel with a gradient system of n-hexane and ethyl acetate. 3.42 g (7.57 mmol, 90%) of the title compound are isolated as a colorless oil.

¹ H-NMR (CDCI3): δ = 1, 10 (9H), 1.53 (1 H), 1, 81 (2H), 1, 96 (3H), 2.71 (3H), 3.59 ( 2H),

D 4.41 (1H), 6.38 (1H), 6.78 (1H), 7.26-7.4θ (6H), 7.65 (2H), 7.72 (2H) ppm .

Example 1 ae

(E, 3S) -3 - [[(1, 1-dimethylethyl) diphenylsilyl] oxy] -4-methyl-5- (2-methylthiazol-4-yl) - pent-4-enal 0 To 1.55 ml of oxaiyl chloride in 14.4 2.73 ml of dimethyl sulfoxide in 11.5 ml of methylene chloride are added dropwise at -70 ° C. ml of methylene chloride. The mixture is stirred for 10 minutes and then 6.0 g of the alcohol described in Example 1 ad are added to 1.5 ml of methylene chloride. After a further 2 hours of stirring, 5.55 ml of triethylamine are added dropwise. The mixture is then allowed to warm to -40 ° C. within one hour and the reaction mixture is then poured into 30 ml of water. The mixture is extracted twice with methylene chloride, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product thus obtained is used in the next step without further purification. 1 H-NMR (CDCI3): δ = 1.09 (9H), 2.01 (3H), 2.51 (1 H), 2.66 (1 H), 2.72 (3H), 4.69 (1 H), 0 6.43 (1 H), 6.81 (1H), 7.3-7.8 (10H), 9.63 (1H) ppm. Example 1 af

(E, 4S, 2RS) -3 - [[(1, 1-dimethylethyl) diphenylsilyl] oxy] -5-methyl-6- (2-methylthiazol-4-yl) hex-5-en-2-ol Zu a solution of 5.9 g of the aldehyde prepared above in 83 ml of 5 tetrahydrofuran is added dropwise at -10 ° C. under nitrogen to 6.94 ml of a 3 molar methylmagnesium chloride solution in tetrahydrofuran. After stirring for 30 minutes at -10 ° C., the reaction mixture is poured onto saturated ammonium chloride solution and extracted three times with ether. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product thus obtained is purified by chromatography on silica gel. With hexane / 0 - 80% ethyl acetate, 5.3 g of the title compound are obtained as a colorless oil.

1 H-NMR (CDCI3): δ = 1.00-1.15 (12H), 1.55-1.90 (2H), 1.90 / 2.04 (3H), 2.69 / 2.72 (3H), 3.90 (1 H), 4.40 / 4.48 (1 H ), 6.23 / 6.51 (1H), 6.69 / 6.80 (1H), 7.20-7.50 (6H), 7.60-7.80 5 (4H) ppm. Example

(E, 4S) -3 - [[(1, 1-dimethylethyl) diphenylsilyl] oxy] -5-methyl-6- (2-methylthiazol-4-yl) - hex-5-en-2-one To a solution of 5 25 g of the alcohol described above in 1 13 ml of acetone, 22 5 ml of Jones reagent are added dropwise at -40 ° C. and the mixture is stirred vigorously. The reaction mixture is allowed to warm to -10 ° C. within one hour, 0 ml of isopropanol is added and the mixture is stirred for another 15 minutes. The mixture is then diluted with ether, washed four times with saturated sodium chloride solution, dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-60% ethyl acetate, 4 01 g of the title compound is obtained as a colorless oil. 1 H NMR (CDCI ₃ ): δ = 1.07 (9H), 1.94 (3H), 2.00 (3H), 2.59 (1 H), 2.70 (3H), 2.74 (1 H), 4.73 (1 H), 6.29 (1H), 6.75 (1H), 7.25-7.50 (6H), 7.60-7.75 (4H) ppm.

Example 1 ah

(1E, 5E / Z, 3S, 10S) -3 - [[(1, 1-dimethylethyl) diphenylsilyl] oxy] -2,5,10-trimethyl-1 - (2-methylithiazol-4-yl) -11 - (tetrahydro-2H-pyran-2-yloxy) -undec-1,5-diene 1.5 ml of a 1 molar solution is added to a solution of 7.24 g of the phosphonium seed described in Example 1v in 80 ml of tetrahydrofuran at 0 ° C. under argon 1 Solution of Natπumbιs (tπmethyisιiylamιd) in tetrahydrofuran and then stirred for 30 minutes at 22 ° C. 2.61 g of the ketone prepared in Example 1 ag in 8 ml of tetrahydrofuran are then added at -40 ° C. and the mixture is stirred at this temperature for 45 minutes. The reaction mixture is poured onto saturated ammonium chloride solution and extracted four times with ether. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue obtained in this way was purified by chromatography on silica gel with those from two further batches in which a total of 3.57 g of the ketone from Example 1 ag were reacted. With hexane / 0-70% ether, 3.7 g of the title compound are obtained as a colorless oil. H-NMR (CDCI3): δ = 0.80-0.92 (3H), 0.92-1.95 (13H), 1.07 (9H), 1.30 / 1.44 (3H), 1.98 / 1.99 (3H), 2.15-2.40 (2H), 2.70 (3H), 3.08 / 3.18 (1H), 3.47-3.62 (2H), 3.85 (1H), 4.27 (1H), 4.55 (1H), 5.05 (1H), 6.19 (1H), 6.78 (1H), 7.24-7.48 (6H), 7.57-7.78 (4H) ppm.

Example 1 ai

(6E / Z, 10E, 2S, 9S) -9 - [[(1, 1-dimethylethyl) diphenylsilyl] oxy] -2,7,10-trimethyl-11 - (2-methylithiazol-4-yi) - undec- 6,10-dien-1-ol

156 mg of pyndinium p-toluenesulfonate are added to a solution of 40 g of the compound prepared in Example 1 ah in 21 ml of ethanol and the mixture is stirred under argon at 50 ° C. for 24 hours. The mixture is then concentrated in vacuo and the residue thus obtained is chromatographed Silica gel cleaned. With hexane / 0-60% ethyl acetate, 2.59 g of the titanium compound is obtained as a colorless oil 1 H-NMR 1 CDCI3): ό = 0.82 / 0.85 (3H), 0.91 (2H), 1.08 (9H), 1.05-1.90 (5H), 1.38 / 1.45 (3H), 2.00, 3H), 2.2C -2.40 (2H), 2.70 (3H), 3.30-3.48 (2H), 4.26 (1 H), 4.98, ^' 5.05 (1 H), 6.15 / 6.18 .1 H), 6.79 (1 H), 7.20-7.50 (6H), 7.60-7.76 (4H) ppm.

Example 1 ak

(6E / Z, 10E.2S, 9S) -9 - [[(1, 1-dimethylethyl) diphenyisilyl] oxy] -2,7,10-trimethyl-1 - (2-methylthiazol-4-yl) -undec- 6,10-dienal

0.729 ml of dimethyl sulfoxide in 3.0 ml of methylene chloride are added dropwise to 0.416 ml of oxalyl chloride in 3.5 ml of methylene chloride at -70 ° C. The mixture is stirred for 10 minutes and then 2.0 g of the alcohol prepared above in 3.0 ml of methylene chloride are added. After a further 2 hours of stirring, 1.49 ml of triethylamine are added dropwise. Then allowed to warm to -40 ° C within one hour and then add the reaction mixture to 15 ml of water. It is extracted twice with methylene chloride, the organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product thus obtained (1.96 g) is used in the next step without further purification.

1 H-NMR (CDCI3): δ = 0.97 / 1.01 (3H), 1.07 (9H), 1.0-2.1 (6H), 1.45 / 1.55 (3H), 2.00 / 2.01 (3H), 2.10-2.48 (3H), 2.69 (3H), 4.25 / 4.27 (1H), 5.01 / 5.03 (1H), 6.16 / 6.17 (1H), 6.79 (1H), 7.25-7.50 (6H), 7.58-7.77 (4H), 9.49 / 9.54 (1H) ppm. Example 1 al

(4S (4R, 5S, 6S, 11 E / Z, 13S, 14E)) - 4- (13 - [[((1, 1-dimethylethyl) diphenylsilyl] oxy] -15- (2-methyl-4-thiazolyl) -3-oxo-5-hydroxy-2,4,6,11,14-pentamethyl-pentadeca-10,14-diene -

2-yl) -2,2-dimethyl- [1, 3] dioxane (A) and

(4S (4R, 5R, 6S, 11 E / Z, 13S, 14E)) - 4- (13 - [[((1, 1-dimethylethyl) diphenylsilyl] oxy] -15- (2-methyl-4-thiazolyl) -3-oxo-5-hydroxy-2,4,6,11, 14-pentamethyl-pentadeca-10,14-dien-2-yl) -2,2-dimethyl- [1, 3] dioxane (B)

1.92 ml of a 2.4 molar solution of butyllithium in hexane are added at -30 ° C. under argon to a solution of 0.62 ml of diisopropylamine in 3 ml of tetrahydrofuran. After stirring for 15 minutes, the mixture is cooled to -70 ° C. and a solution of 857 mg of the compound prepared according to Example 11 in 3 ml of tetrahydrofuran is added dropwise. After stirring for one hour, 500 mg of the aldehyde prepared in Example 1 ak in 3 ml of tetrahydrofuran are added dropwise. After stirring at this temperature for 1.5 hours, the reaction mixture is poured onto saturated ammonium chloride solution and extracted several times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-50% ether, 1.62 g of the titan compound (A) is obtained as a colorless oil, and 0.12 g of the diastereomeric compound B as a pale yellow-colored oil. 1 H-NMR (CDCI3) of A: δ = 0.75 / 0.79 (3H), 1.00 / 1 .01 (3H), 1 .05 (9H), 1.09 / 1 .10 (3H), 1 .20 (3H) , 1.30 / 1.43 (3H), 1.35 (3H), 1.43 (3H), 0.30-1.95 (10H), 1.96 / 1.99 (3H), 2.03-2.40 (2H), 2.70 (3H), 3.18- 3.40 (2H), 3.80-4.09 (3H), 4.27 (1H), 5.06 (1H), 6.18 (1H), 6.79 (1H), 7.22-7.48 (6H), 7.58-7.77 (4H) ppm . H-NMR (CDCl3) of B: δ = 0.80-2.80 (18H), 1.02 (3H), 1 .08 (12H), 1.28 (3H), 1.33 (3H), 1.41 / 1 .42 (3H), 1.97 / 1.98 (3H), 2.71 (3H), 3.13-3.57 (2H), 3.75-4.15 (3H), 4.26 (1H), 5.03 (1H), 6.18 (1H), 6.78 (1H) , 7.22-7.50 (6H), 7.53-7.70 (4H) ppm. Example 1 on (4S (4R, 5S, 6S, 11 E / Z, 13S, 14E)) - 4- (13 - [[(1, 1-dimethylethyl) diphenyisilyl] oxy] -15- (2-methyl-4 -thiazolyl) -3-oxo-5- (tetrahydropyran-2-yloxy) -2,4,6,11, 14-pentamethyl-pentadeca-10,14-dien-2-yl) -2,2-dimethyl- [ 1, 3] dioxane

200 mg of p-toluenesulfonic acid monohydrate and 3.03 ml of dihydropyran are added to a solution of the title compound A prepared above in 30 ml of methylene chloride and the mixture is stirred at 22 ° C. for 3 days. Then the reaction mixture is poured onto saturated sodium bicarbonate solution and extracted with methylene chloride. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-40% ethyl acetate, 1.53 g of the title compound is obtained as a colorless oil. H-NMR (CDCI3): δ = 0.8-2.55 (37H), 1.06 (9H), 1.96 / 1.98 (3H), 2.69 (3H), 3.10-4.15 (8H), 4.26 (1H), 4.40-4.63 (1H), 5.05 (1H), 6.17 (1H), 6.78 (1H), 7.21-7.48 (6H), 7.55-7.74 (4H) ppm.

Example 1an (4S (4R, 5S, 6S, 11 E / Z, 13S, 14E)) - 4- (13-hydroxy-15- (2-methyl-4-thiazolyl) -3-oxo-5- (tetrahydropyran 2-yloxy) -2,4,6,11,14-pentamethyl-pentadeca-10,14-dien-2-yl) -2,2-dlmethyl- [1, 3] dioxane

5.34 ml of a 1 molar solution of tetrabutyiammonium fluoride in tetrahydrofuran are added to a solution of the compound prepared above in 50 ml of tetrahydrofuran and the mixture is first stirred at 22 ° C. for 12 hours and then at 50 ° C. for 4 hours. Then the reaction mixture is poured onto saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-80% ethyl acetate, 851 mg of the title compound is obtained as a colorless oil.

1 H-NMR (CDCI3): δ = 0.80-2.60 (39H), 2.07 (3H), 2.73 (3H), 3.28 (1 H), 3.45 (1 H), 3.60- 4.33 (6H), 4.43- 4.61 (1H), 5.25-5.43 (1H), 6.60 (1H), 6.95 (1H) ppm.

Example 1 ao (3S, 6R, 7S, 8S, 12E / Z.15S.16E) -17- (2-methyl-4-thiazolyi) -5-oxo-4,4,6,8,13.16-hexamethyi-heptadeca-12, 16-diene-1, 3,7,15-tetraol

445 mg of p-toluenesulfonic acid monohydrate are added to a solution of 725 mg of the alcohol prepared above in 33 ml of ethanol and the mixture is stirred under nitrogen at 22 ° C. for 3 hours. Then the reaction mixture is poured onto saturated sodium bicarbonate solution and extracted with methylene chloride. The organic phase is dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-100% ethyl acetate / 0-10% methanol, 505 mg of the titanium compound is obtained as a colorless oil. ¹ H-NMR (CDCI3): δ = 0.84 / 0.87 (3H), 1.07 (3H), 1.13 (3H), 1.23 (3H), 1.68 / 1.77 (3H), 1.00-1.85 (10H), 2.06 (3H) , 2.08-2.6 (3H), 2.72 (3H), 3.20-3.51 (4H), 3.89 (2H), 4.05 (1 H), 4.23 / 4.29 (1 H), 5.30 / 5.40 (1 H), 6.61 (1 H), 6.96 / 6.97 (1H) ppm.

Example 1 ap (3S, 6R, 7S, 8S, 12E / Z, 15S, 16E) -17- (2-methyl-4-thiazolyl) -4,4,6,8,13,16-hexamethyi- 1,3 , 7,15-tetrakis - [[dimethyl- (1, 1-dimethylethyl) siiyi] oxy] -heptadeca-12,16-dien-5-one

To a solution of 490 mg of the tetrol prepared above in 30 ml of methylene chloride, 4 ml of 2,6-lutidine are added at -70 ° C. under argon and then 3.9 ml of tert.butyldimethylsilyl ester of fluoromethanesulfonate are added dropwise and the mixture is stirred at -70 ° C. for 24 hours . Then the reaction mixture is poured onto saturated sodium bicarbonate solution and extracted with methylene chloride. The organic phase is dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-50% ethyl acetate, 742 mg of the titanium compound is obtained as a colorless oil. ^" Η NMR (CDCI3): δ = 0.00-0.15 (24H), 0.90 (39H), 0.95-1, 75 (9H), 1.05 (3H), 1.06 (3H), 1.22 (3H), 1.53 / 1. 62 (3H), 2.00 / 2.02 (3H), 2.21 (2H), 2.71 (3H), 3.15 (1H), 3.58 (1H), 3.67 (1H), 3.77 (1H), 3.90 (1H ), 4.23 (1 H), 5.18 (1 H), 6.49 (1 H), 6.92 / 6.93 (1 H) ppm.

Example 1aq (3S, 6R, 7S, 8S, 12E / Z, 15S, 16E) -17- (2-methyl-4-thiazolyl) -4,4,6,8,13,16-hexamethyl-1-hydroxy- 3,7,15-tris - [[dimethyl- (1, 1-dimethylethyl) silyi] oxy] -heptadeca-12,16-dien-5-one

179 mg of camphor-10-sulfonic acid are added at 0 ° C. under argon to a solution of 735 mg of the silyl ether prepared above in a mixture of 8 ml of dichloromethane and 8 ml of methanol, and the mixture is allowed to warm to 22 ° C. and is stirred for a further 1.5 hours Then 0.6 ml of triethylamine is added, poured into a saturated sodium hydrogen carbonate solution and extracted several times with dichloromethane. The organic phase is dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is chromatographed on silica gel cleaned. With hexane / 0-20% ethyl acetate, 527 mg of the title compound is obtained as a colorless oil.

¹ H-NMR (CDCI3): δ = 0.00-0.17 (18H), 0.93 (30H), 1.09 (9H), 0.90-1.54 (8H), 1.66 / 1.73 (3H), 1.93 (2H), 2.00 / 2.03 (3H), 2.20 (2H), 2.73 (3H), 3.15 (1H), 3.67 (2H), 3.81 (1H), 4.10 (1H), 4.23 (1H), 5.20 (1H ), 6.47 (1 H), = 6.92 / 6.94 (1 H) ppm.

Example 1 ar

(3S, 6R, 7S, 8S, 12E / Z, 15S, 16E) -17- (2-methyl-4-thiazolyl) -4,4,6,8,13,16-hexamethyl-3,7,15- tris - [[dimethyl- (1, 1-dimethylethyl) silyl] oxy] -5-oxo-heptadeca-12,16-dienal To a solution of 520 mg of the alcohol prepared above in 30 ml of methyl chloride is added at 0 ° C. Argon 1.28 g Collins reagent and stir at 0 ° C for 15 minutes. Then Celite is added and the mixture is diluted with ether. It is filtered off through Celite, washed well with ether and the filtrate is concentrated in vacuo. The title compound (463 mg) thus obtained is used in the next step as a pale yellow oil without further purification.

^" Η NMR (CDCI3): δ = 0.0-0.17 (18H), 0.91 (30H), 1.05 (3H), 1.10 (3H), 1.27 (3H), 1.65 / 1.72 (3H), 1.00-1.62 (8H) , 2.00 / 2.03 (3H), 2.21 (2H), 2.30-2.58 (3H), 2.72 (3H), 3.14 (1 H), 3.79 (1 H), 4.23 (1 H), 5.20 (1 H), 6.47 (1H), 6.92 / 6.94 (1H) ppm.

Example l as

(3S, 6R, 7S, 8S, 12Z, 15S, 16E) -17- (2-ethyl-4-thiazolyl) -4,4,6,8,13,16-hexamethyl-

3,7,15-tris - [[dimethyl- (1,1-dimethylethyl) silyl] oxy] -5-oxo-heptadeca-12,16-dienoic acid

(A) and

(3S, 6R, 7S, 8S, 12E, 15S, 16E) -17- (2-methyl-4-thiazolyl) -4,4,6,8,13,16-hexamethyl-3,7,15-tris- [[dimethyl- (1,1-dimethylethyl) silyl] oxy] -5-oxo-heptadeca-12,16-dienoic acid

(B)

To a solution of 530 mg of the aldehyde prepared above in 19.5 ml of acetone, 1.5 ml of a standardized 8N chromosulfuric acid solution are added at -30 ° C. and the mixture is stirred for 45 minutes. It is poured into a mixture of water and diethyl ether and the organic phase is washed twice with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel twice. With hexane / 0-90% ethyl acetate, 162 mg of the title compound A are obtained as a non-polar component and 171 mg of the title compound B as a polar component as colorless oils. H-NMR (CDCI3) of A: δ = 0.00-0.18 (18H), 0.88 (30H), 0.90-1 .68 (7H), 1.09 (3H), 1.17 (3H), 1.20 (3H), 1.75 (3H ), 1.98 (3H), 2.00-2.50 (4H), 2.72 (3H), 3.16 (1 H), 3.73 (1 H), 4.33 (1 H), 4.43 (1 H), 5.23 (1 H), 6.72 (1H), 6.97 (1H) ppm. 1 H-NMR (CDCI3) of B: δ = 0.00-0.17 (18H), 0.90 (30H), 0.90-1.45 (7H), 1.07 (3H), 1.13 (3H), 1.23 (3H ), 1.63 (3H), 1.97 (3H), 1.85-2.58 (4H), 2.51 (3H), 3.17 (1H), 3.80 (1H), 4.21 (1H), 4.39 (1H ), 5.18 (1H), 6.46 (1H), 6.92 (1H) ppm.

Example 1 at

(3S, 6R, 7S, 8S, 12E.15S, 16E) -17- (2-ethyl-4-thiazolyl) -4,4,6,8,13,16-hexamethyl-3,7- bis - [[ dimethyl- (1,1-dimethylethyl) silyl] oxy] -15-hydroxy-5-oxo-heptadeca-12,16-dienoic acid

0.59 ml of a 1 molar solution of tetrabutylammonium fluoride is added to a solution of 50 mg of the title compound B prepared in Example las in 1.5 ml of tetrahydrofuran at 22 ° C. under argon and the mixture is stirred for 16 hours. Then the reaction mixture is poured onto ice-cold saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic phases are washed once with 1 N hydrochloric acid and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane 7 0-80% ethyl acetate, 42 mg of the title compound is obtained as a colorless oil.

1 H-NMR (CDCI3): δ = 0.00-0.15 (12H), 0.91 (21 H), 1.07 (3H), 1.13 (3H), 1.23 (3H), 0.80-1.50 (9H), 1.69 (3H), 2.03 (3H), 2.1 1-2.58 (4H), 2.73 (3H), 3.15 (1 H), 3.80 (1 H), 4.24 (1 H), 4.41 (1 H), 5.31 (1 H), 6.53 ( 1 H), 6.95 (1 H) ppm.

Example 1 au

(4S, 7R, 8S, 9S, 13E, 16S (E)) - 4,8-bis - [[dimethyl- {1, 1-dimethylethyl) silyl] oxy] -16- (1-methyl-2- (2nd -methyl-4-thiazolyl) ethenyl) -1-oxa-5,5,7,9,14-pentamethyl-cyclohexadec-13-ene-2,6-dione

75 μl of triethylamine, 50 μl of 2,4,6-trichlorobenzoyichloride are added to a solution of 118 mg of the acid prepared above in 6 ml of tetrahydrofuran under argon and the mixture is stirred for 15 minutes. This solution is added dropwise to a solution of 195 mg of 4-dimethylaminopyridine in 90 ml of toluene within 3 hours and the mixture is stirred at 23 ° C. for a further 15 minutes. It is concentrated in vacuo and the residue thus obtained is purified by chromatography on silica gel. With hexane / 0-40% ethyl acetate, 87 mg of the title compound is obtained as a colorless oil.

1 H-NMR (CDCI3): δ = 0.00-0.17 (12H), 0.87 (9H), 0.93 (9H), 0.96 (3H), 1.12 (3H), 1.14 (3H), 1 .21 (3H), 1 .63 (3H), 2.14 (3H), 1 .00-2.37 (10H), 2.49 (1 H), 2.62 (1 H), 2.73 (1 H), 2.82 (1 H), 3.05 (1 H), 3.92 (1H), 4.20 (1H), 5.31 (1H), 5.37 (1H), 6.59 (1H), 6.95 (1H) ppm.

example 1 (4S, 7R, 8S, 9S, 13E, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-thiazoiyl) ethenyl) -1-oxa-5, 5,7,9,14-pentamethyl-cyclohexadec-13-ene-2,6-dione

348 μl of a 20% strength solution of trifluoroacetic acid in methylene chloride are added to a solution of 45 mg of the lactone prepared above in 1.5 ml of methylene chloride at -10 ° C. under argon. The mixture is allowed to warm to 0 ° C. and is stirred at this temperature for 5 hours. The reaction mixture is then concentrated in vacuo and the residue thus obtained is purified by chromatography on silica gel. With hexane / 0-80% ethyl acetate, 22.4 mg of the title compound is obtained as a colorless oil. 1 H-NMR (CDCI3): δ = 0.99 (3H), 1.08 (3H), 1.20 (3H), 1.31 (3H), 1.64 (3H), 1.05-1.75 (5H), 1.90 (1 H), 2.01 ( 3H), 2.21 (2H), 2.34 (1 H), 2.49-2.52 (3H), 2.72 (3H), 3.10 (1 H), 3.22 (1 H), 3.77 (1 H), 4.02 (1 H), 5.31 (1H), 5.52 (1H), 6.58 (1H), 6.98 (1H) ppm.

Example 2

(1 S, 3S (E), 7S, 10R, 11 S, 12S, 16S) -7.11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1, 8,8,10,12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (A) and

(1 R, 3S (E), 7S, 10R, 11 S, 12S, 16R) -7.11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazoiyl) ethenyl) -1, 8,8,10,12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (B) To a solution of 20 mg of the title compound prepared according to Example 1 in 0.4 ml of acetonitrile is added at 0 ° C under argon 233 μl of a 0.1037 molar EDTA-di-sodium salt solution and 389 μl 1, 1, 1-trifluoroacetone. A mixture of 47.6 mg oxone and 27.3 mg sodium hydrogen carbonate is then added and the mixture is stirred at 0 ° C. for 2.5 hours. Then sodium thiosulfate solution is added and the mixture is extracted several times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and, after filtration, concentrated in vacuo. A second batch of the same size provides another batch of raw product. The combined crude products thus obtained are pre-cleaned by preparative thick layer chromatography with hexane / 50% ethyl acetate. The actual separation of the title compounds A and B is carried out by HPLC separation (Chiralpak AD 10μ; hexane: ethanol 85:15). In this way, 6.7 mg of the title compound A and 16.2 mg of the titite compound B are obtained as colorless oils.

1 H NMR (CDCI3) of A: δ = 0.99 (3H), 1.05 (3H), 1.16 (3H), 1.43 (3H), 1.45 (3H), 1.05-1.72 (8H), 2.00 ( 2H), 2.09 (3H), 2.44 (2H), 2.72 (3H), 2.89 (1 H), 3.50 (1 H), 3.83 (1 H), 4.14 (1 H), 4.50 (1 H), 5.62 ( 1 H), 6.57 (1 H), 6.98 (1 H) ppm.

1 H-NMR (CDCI3) of B: δ = 1.03 (3H), 1.13 (3H), 1.23 (3H), 1.34 (3H), 1.36 (3H), 1.07- 1.72 (7H), 1.70 (1 H), 2.08 (3H), 2.22 (2H), 2.50 (1 H), 2.60 (1 H), 2.72 (3H), 2.93 (1 H), 3.25 (1 H), 3.57 (1 H), 3.82 (1 H) , 4.05 (1H), 5.44 (1H), 6.66 (1H), 6.98 (1H) ppm. Example 3

(4S, 7R, 8S, 9S, 13Z.16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5,7,9,14-pentamethyl-cyclohexadec-13-ene-2,6-dione

Example 3a

(3S, 6R, 7S, 8S, 12Z, 15S, 16E) -17- (2-methyl-4-thiazolyl) -4,4,6,8,13,16-hexamethyl-3,7- bis - [[ dimethyl- (1,1-dimethylethyl) silyl] oxy] -15-hydroxy-5-oxo-heptadeca-12,16-dienoic acid

Analogously to Example 1s, 150 mg of the title compound A prepared in Example 1r are reacted. 81 mg of the titanium compound are obtained as a colorless oil.

1 H-NMR (CDCI3): δ = 0.00-0.16 (12H), 0.90 (21 H), 1.08 (3H), 1.17 (3H), 1.18 (3H), 0.80-2.28 (8H), 1.78 (3H), 2.03 (3H), 2.30-2.55 (4H), 2.73 (3H), 3.14 (1 H), 3.78 (1 H), 4.28 (1H), 4.42 (1 H), 5.38 (1 H), 6.78 (1 H ), 6.97 (1H) ppm.

Example 3b

(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-bis - [[dimethyl- (1, 1-dimethylethyl) silyi] oxy] -16- <1 - methyl-2- (2 -methyl-4-thiazolyl) ethenyl) -1-oxa-5,5,7,9,14-pentamethyl-cyclohexadec-

13-en-2,6-dione

Analogously to Example 1au, 81 mg of the compound prepared above are reacted. 75 mg are obtained after column chromatography, which are again purified by preparative thick-layer chromatography with hexane / 10% ethyl acetate.

58 mg of the title compound are obtained as a colorless oil.

1 H-NMR (CDCI3): δ = 0.00-0.17 (12H), 0.79-0.99 (24H), 1.09 (3H), 1.16 (3H), 1.72 (3H),

1.00-1.92 (8H), 2.12 (3H), 2.31 (2H), 2.68 (1 H), 2.71 (1 H), 2.88 (1 H), 2.99 (2H), 3.89 (1 H), 3.98 (1 H ), 5.06 (1H), 5.27 (1H), 6.59 (1H), 6.98 (1H) ppm.

Example 3

(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-thiazoiyl) ethenyi) -1-oxa-5, 5,7,9,14-pentamethyl-cyclohexadec-13-en-2,6-dione In analogy to Example 1, 27 mg of the compound prepared above are reacted. The purification is carried out by preparative thick-layer chromatography with hexane / 20% ethyl acetate. 17.4 mg of the title compound are obtained as a colorless oil. 1H-NMR (CDCI3): δ = 1.02 (3H), 1.11 (3H), 1.20 (3H), 1.35 (3H), 1.75 (3H), 1.10-2.05 (7H), 2.10 (3H), 2.20 (1H ), 2.39 (1 H), 2.51 (1 H), 2.70 (3H), 2.83-3.01 (2H), 3.14 (1 H), 3.80 (1 H), 3.42 (1 H), 4.20 (1 H), 5.23 (1H), 5.40 (1H), 6.62 (1H), 6.98 (1H) ppm.

Example 4 (1 R, 3S (E), 7S, 10R, 11 S, 12S, 16S) -7.11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazoiyl) ethenyl) -1, 8,8,10,12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (A) and

(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-thiazolyi) ethenyl) -1, 8 , 8, 0,12-pentamβtByl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (B)

Analogously to Example 2, 15 mg of the compound prepared in Example 3 are reacted. The purification is carried out only by preparative thick layer chromatography.

0.3 mg of the title compound A and 11 mg of the title compound B are obtained as colorless oils.

1H-NMR (CDCI3) of A: δ = 0.94 (3H), 1.04 (3H), 1.10 (3H), 1.41 (3H), 1.43 (3H), 1.05-

2.20 (7H), 2.12 (3H), 2.24-2.65 (4H), 2.73 (3H), 3.32 (1H), 3.40-3.82 (2H), 4.07 (1H),

5.80 (1H), 6.62 (1H), 6.98 (1H) ppm.

1H-NMR (CDCI3) of B: δ = 1.03 (3H), 1.15 (3H), 1.21 (3H), 1.36 (3H), 1.38 (3H), 1.10-1.97 (9H), 2.05 (3H), 2.09 ( 1H), 2.42 (1H), 2.53 (1H), 2.70 (3H), 2.72 (1H), 3.14 (1H),

3.67 (1H), 3.81 (1H), 4.12 (1H), 5.49 (1H), 6.56 (1H), 6.97 (1H) ppm.

Claims

claims

1. epothilone derivatives of the general formula I,

I, in which

Rl a Rl b are identical or different and are hydrogen, Cj-Ci Q-alkyl, aryl, C7-C20-aralkyl, or together a - (CH2) _m group with m = 2, 3, 4 or 5,

R ^2a , R2k are the same or different and are hydrogen, C-ι-C- | o-alkyl, aryl, C7-C20-aralkyl or together a - (CH2) _n group with n = 2, 3, 4 or 5,

R ^{3 is} hydrogen, Cι -C- | o- ^A 'kyl. Aryl, C7-C20 aralkyl,

R4a _> 4b are identical or different and are hydrogen, C1-C10-alkyl, aryl, C7-C20-aralkyl or together a - (CH2) _p group with p = 2, 3, 4 or 5,

H ₂ C-CH ₂ , HC = CH, c≡C, _{H (CH} ,

DE a group

R5 CI-C 1-10 -alkyl, aryl, C7-C20-aralkyl,

R6, R? each a hydrogen atom, together an additional bond or an oxygen atom,

R25 is hydrogen, C-1 -C1 o-alkyl, where the alkyl radical can optionally be substituted by one or more haiogen atoms and / or hydroxyl groups, RÖ is hydrogen, C- | -C20-alkyl, aryl, C7-C20- ralkyl, which can all be substituted, X is an oxygen atom, two alkoxy groups OR ⁹ , a C2-Cι o- ^A ' ^k y ^| en-α, ω- dioxy group, which can be straight-chain or branched, H / OR ^ O or a grouping CR ^{1 1} R ^{1 2} , where

R ⁹ for a -C -C20 alkyl radical, R ¹⁰ for hydrogen or a protective group PG, R11, R ¹ 2 are the same or different and, for hydrogen, a C- | -C20-alkyl, aryl, C7-C20-aralkyl radical or R ^{1 1} and R ^{1 2} 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 ³ , where

R ^{1 is} hydrogen or a protective group PG2, including all stereoisomers of these compounds and mixtures thereof.

2. epothilone derivatives of the general formula I according to claim 1, wherein R ³ , R ^4a , R ^4b , DE, R ⁵ , R ⁶ , R25 and R ^{7 can} all have the meanings given in the general formula I, and the rest of the molecule is identical to the naturally occurring epothilone A or B.

3. epothilone derivatives of the general formula I according to claim 1, wherein R5, R6, R25 _t R ^, R8 and X can all have the meanings given in the general formula I, and the rest of the molecule is identical to the naturally occurring epothilone A or B.

4. epothilone derivatives of the general formula I according to claim 1, wherein Y, Z, R ^{1 a} , Rlb R a, R2, R3, R4a, _R 4b _? DE, R5, R6, R25 _{and R} 7 _a | _{ie the} j _π of the general formula may have the meanings indicated I, and the remainder of the molecule is identical with the naturally occurring epothilones A or B.

5. epothilone derivatives of the general formula I according to claim 1, wherein Y, Z, R ^{1 a} , R ¹ _, R ^2a , R2b _τ R5, R6_ R25_ R7 R8 _and x _{a (} | _{e dje jn in the} general formula I given meanings and the rest of the molecule is identical to the naturally occurring epothilone A or B.

6. epothilone derivatives of the general formula I according to claim 1, wherein R ³ , R ^ ^a , R ^4b , DE, R ⁵ , R ⁶ , R ²⁵ , R7_ R8 _uπ x _a || _ed j _{e ιn the} general formula! may have the meanings given, and the rest of the molecule is identical to the naturally occurring epothilone A or B.

7. epothilone derivatives of the general formula I according to claim 1, wherein R ^ stands for a methyl, ethyl or propylene group.

8. epothilone derivatives of the general formula I according to claim 7, wherein R ^ and R ⁷ together mean an additional bond.

9. epothilone derivatives of the general formula I according to claim 7, wherein R ⁶ and R ⁷ together represent an epoxy group.

10. epothilone derivatives of the general formula I according to claim 1, wherein R25 represents a hydrogen atom, a methyl, ethyl, propyl, hydroxymethyl, fluoromethyl or trifluoromethyl group.

11. Compounds of general formula I according to claim 1, namely

(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-thiazoiyl) ethenyl) -1-oxa-5, 5,7,9,14-pentamethyl-cyclohexadec-13-ene-2,6-dione

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

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

(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-oxazolyl) ethenyl) -1 - oxa-5, 5,7,9,14-pentamethyl-cyclohexadec-13-ene-2,6-dione (1 S, 3S (E), 7S.10R, 1 1 S, 12S, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-oxazolyl) ethenyl) -1.3 .3,10,12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and

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

(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-oxa- 5,5,7, 9, 14-pentamethyl-cyclohexadec-13-en-2,6-dione

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

(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-Dihydroxy-7-ethyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1- oxa-5,5,9,14-tetramethyl-cyclohexadec-13-ene-2,6-dione

(1 S, 3S (E), 7S, 10R, 11 S, 12S, 16R) -7,11-dihydroxy-10-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyi ) -1, 8,8,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and (1 R, 3S (E), 7S, 10R, 11 S, 12S, 16S) -7,11-dihydroxy-10-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1,8,8,12-tetramethyl-4,17-dioxabicyclo [14.1. 0] heptadecane-5,9-dione

(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-5,5-dimethylene-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 1-oxa-7,9,14-trimethyl-cyclohexadec-13-ene-2,6-dione

(1S, 3S (E), 7S, 10R, 11 S, 12S, 16R) -7,11-dihydroxy-8,8-dimethylene-3- (1-methyl-2- (2-methyl-4-thiazoiyl) ethenyl) -1, 10,12-trimethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and (1R, 3S (E), 7S, 10R, 11 S, 12S, 16S) -7 , 11-Dihydroxy-8,8-dimethylene-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1, 10,12-trimethyl-4, 17-dioxabicyclo [14.1.0] heptadecan-5,9-dione

(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-Dihydroxy-5,5-trimethyien-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 1-oxa-7,9,14-trimethyl-cyclohexadec-13-ene-2,6-dione

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

(1 R, 3S (E), 7S, 10R, 1 1 S, 12S, 16S) -7,11-dihydroxy-8,8-trimethylene-3- (1-methyl-2- (2-methyl-4- thiazolyl) ethenyl) - 1, 10,12-trimethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione (4S, 7R, 3S, 9S.13Z.16S (E)) - 4, S-Dihydroxy-14-ethyl-16- (1-methyl-2- (2-methyi-4-thiazolyi) ethenyl) -1- oxa-5,5,7,9-tetramethyi-cyclohexadec-13-ene-2,6-dione

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

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

(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-Dihydroxy-14-ethyl-16- (1-methyl-2- (2-methyl-4-oxazolyl) ethenyl) -1- oxa-5,5,7,9-tetramethyl-cyclohexadec-13-ene-2,6-dione

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

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

(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-14-ethyl-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-oxa-5, 5,7,9-tetramethyl-cyclohexadec-13-ene-2,6-dione

(1S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-1-ethyl-3- (1-methyl-2- (2-pyridyl) ethenyl) -8.8, 10,12-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and (1 R, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy- 1-ethyl-3- (1-methyl-2- (2-pyridyl) ethenyl) -8.8, 10.12-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione

(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-dihydroxy-7,14-diethyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 1-oxa-5,5,9-trimethyi-cyclohexadec-13-en-2,6-dione

(1S, 3S (E), 7S _, 10R _, 11 S, 12S, 16R) -7,11-dihydroxy-1 _, 10-diethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -8,8,12-trimethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and (1R, 3S (E), 7S, 10R _, 11 S, 12S, 16S) -7 , 11-Dihydroxy-1, 10-diethyi-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -8,8,12-trimethyl-4,17-dioxabicyclo [14.1.0] heptadecan-5,9-dione

(4S, 7R, 8S, 9S, 13Z, 16S (E)) - 4,8-Dihydroxy-14-proyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1- oxa-5,5,7,9-tetramethyl-cyclohexadec-13-ene-2,6-dione (1S, 3S (E), 7S, 10R, 11 S, 12S.16R) -7,11-dihydroxy-1-propyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -8,3,10,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and

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

(4S, 7R, 8S, 9S, 13E, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1-oxa-5, 5,7,9,14-pentamethyl-cyclohexadec-13-ene-2,6-dione

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

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

(4S, 7R, 8S, 9S, 13E, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methyl-4-oxazolyl) ethenyl) -1-oxa-5, 5,7,9,14-pentamethyl-cyclohexadec-13-ene-2,6-dione

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

(1 R, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-3- (1-methyl-2- (2-methyl-4-oxazol1yl) ethenyl) -1, 8 , 8, 10,12-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione

(4S, 7R, 8S, 9S, 13E, 16S (E)) - 4,8-dihydroxy-16- (1-methyi-2- (2-pyridyl) ethenyl) -1-oxa- 5,5,7, 9,14-pentamethyl-cyclohexadec-13-ene-2,6-dione

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

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

(4S, 7R, 8S, 9S, 13E, 16S (E)) - 4,8-dihydroxy-7-ethyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1- oxa-5,5,9,14-tetramethyl-cyclohexadec-13-ene-2,6-dione

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

(4S, 7R, 8S, 9S, 13E, 16S (E)) - 4,8-dihydroxy-14-ethyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1- oxa-5,5,7,9-tetramethyl-cyclohexadec-13-ene-2,6-dione

(1S, 3S (E), 7S, 10R, 11S, 12S, 16S) -7,11-dihydroxy-1-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) - 8,8,10,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione and (1R, 3S (E), 7S, 10R, 11S, 12S, 16R) -7.11 -Dihydroxy-1-ethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -8,8,10,12-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane 5,9-dione

(4S, 7R, 8S, 9S, 13E, 16S (E)) - 4,8-dihydroxy-14-proyl-16- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl) -1- oxa-5,5,7,9-tetramethyl-cyclohexadec-13-ene-2,6-dione

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

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

12. 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 B

B where

R ³ '. R ^4a ', R ^4b ' and R ^{25 have} the meanings already given for R ³ , R ^4a - R ⁴ and R ²⁵ , and

R ^{17 is} a hydroxy group, halogen, a protected hydroxy group OPG ³

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 (0) Ph2 (Ph = phenyl), mean

with a fragment of the general formula C

wherein

R5 ^' , R8' _d each have the _meaning already mentioned in the general formula I for R5 and R ³ and R20 _e j _{n is a} hydrogen atom or a protective group PG ⁵ U is an oxygen atom, two alkoxy groups OR ⁹ , a C2-C- | o ^-A l ^k yl ^en - ^α _' ^ω - dioxy group, which can be straight-chain or branched, H / OR 10 or one

Grouping CR ¹ R ¹ 2, where

R ⁹ for a C ¹ -C 20 -alkyl radical, R ^{1 (3} for hydrogen or a protective group PG ^,

R1 ¹ , R ^{1 2 are the} same or different and, for hydrogen, a C- | -C20 alkyl, aryl, C7-C20 aralkyl radical or R ^{1 1} and R ¹² together with the methylene carbon atom together for a 5- to 7-membered carbocyclic ring

W is an oxygen atom, two alkoxy groups OR ²¹ , a C2-C- | o-alkylene-α, ω- dioxy group, which can be straight-chain or branched, or H / OR ²² , stand where

R ²¹ for a -C20-alkyl radical,

R ^{22 represents} hydrogen or a protective group PG ⁷ ,

to a partial fragment of the general formula BC

BC,

wherein

R ³ , R ^4a , R ⁴ , R ⁵ , R ⁶ , R ²⁵ , R ⁷ , R ²⁰ , D, E, U and V have the meanings already mentioned, and implemented this partial fragment BC with a fragment of the general formula A.

A,

wherein

Rl ^a ', Rl', R ^2a 'and R ² ' have the meanings already mentioned for R ^{1 a} , R ^{1 b} , R ^a and R ^2b and

R1 CH ₂ OR ^14a , CH ₂ -Hal, CHO, CO ₂ R ^14b , COHal,

R15 hydrogen, OR1 ^5a , shark, OSO ₂ R ^{1 5b} ,

Rl4a l 5a hydrogen, Sθ2-alkyl, Sθ2-aryl, Sθ2-aralkyl or together a - (CH2) o group or together a CR ^{1 6a} R ^{1 6b} group, R ^14b , R ^{1 5b} hydrogen, C- | - C20-alkyl, aryl, C7-C20-raikyl,

Rl 6a _? Rl 6b are the same or different and are hydrogen, C-ι-C- | o-alkyl, aryl, C7-C20-aralkyl, or together a - (CH2) q group,

Shark halogen, o 2 to 4, q 3 to 6, including all stereoisomers and their mixtures mean as well free hydroxyl groups in R ^ ⁴ and R ¹ 5 etherified or esterified, free carbonyl groups in A and R ^* * ketalized, converted into an enol ether or reduced, and free acid groups in A in whose salts can be converted with bases,

to a partial fragment of the general formula ABC

ABC,

wherein Rl ^a , R ^{1 b} , R ^2a , R ² , R ³ , R ^4a , R ^4b , R ⁵ , R6, R ² 5, R ⁷ , R8, R14 R1 5, D, E, U and Z the already have meanings mentioned, implemented and this partial fragment of the general formula ABC is cyclized to an epothiione derivative of the general formula.

13. Intermediates of the general formula B

B where

R ³ '- R ^4a ', R ⁴ 'and R ²⁵ ' have the meanings already given for R ³ , R ^a , R and R ²⁵ , and R ^{1 7 is} a hydroxyl group, halogen, a protected hydroxyl group OPG ³

Phosphonium halide residue PPh3 ⁺ Hal ^_ (Ph = phenyl; Hai = F, Cl, Br, I), a phosphonate residue P (0) (OQ) 2 (Q = C- | -C- | o-alkyl or phenyl) or a phosphine oxide residue P (0) mean Ph2 (Ph = phenyl).

14. Intermediates of the general formula C

wherein

R5 ^' , RÖ ^{* have} the meaning already given in the general formula I for R ⁵ and R ⁸ and R ^{20 is} a hydrogen atom or a protective group PG ⁵

U one oxygen atom, two alkoxy groups OR ⁹ , one C2-C- | o-alkylene-α, ω-dioxy group, which can be straight-chain or branched, H / OR ^{1 0} or one

Grouping CR ^{1 1} R ¹² , where

R ^{9 represents} a C 1 -C 20 -alkyl radical,

R ¹ 0 for hydrogen or a protective group PG ⁶ ,

R1 1, R ^{12 are the} same or different and for hydrogen, a C1-C20-alkyl, aryl, C7-C20-aralkyl radical or R ^{1 1} and R ^{1 2} together with the methylene carbon atom together for a 5- to 7-membered carbocyclic ring W one oxygen atom, two alkoxy groups OR ²¹ , one C2-C-ιo- ^A 'kyl ^{er |} - < ^χ , ω- dioxy group, which can be straight-chain or branched or H / OR ²² , where

R ^{2 "1} for a C ¹ -C 20 -alkyl radical,

R ^{22 represents} hydrogen or a protective group PG ⁷ .

15. Intermediates of the general formula BC

BC, well R ³ , R ^4a , R ^4b , R ⁵ , R ⁶ , R ²⁵ , R ⁷ , R ²⁰ , D, E, U and V have the meanings already mentioned.

16. Intermediates of the general formula ABC

ABC,

wherein Rl ^a , Rl ^b , R ^a , R ² , R ³ , R ^a , R ^b , R5, R6, R25, _R 7_R8, _R U R15 _{ID) E>} y _and d Z have the meanings already mentioned.

17. Pharmaceutical preparations containing at least one compound of general formula I according to claim 1 and a pharmaceutically acceptable carrier.

18. Use of the compounds of general formula I according to claim 1 for the manufacture of medicaments.