WO2001066154A2 - Radioactively labeled epothilone derivatives, method for the production thereof, and their biochemical and pharmaceutical use - Google Patents

Radioactively labeled epothilone derivatives, method for the production thereof, and their biochemical and pharmaceutical use Download PDF

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Publication number
WO2001066154A2
WO2001066154A2 PCT/EP2001/002699 EP0102699W WO0166154A2 WO 2001066154 A2 WO2001066154 A2 WO 2001066154A2 EP 0102699 W EP0102699 W EP 0102699W WO 0166154 A2 WO0166154 A2 WO 0166154A2
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Prior art keywords
dione
dihydroxy
tetramethyl
ethenyl
methyl
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PCT/EP2001/002699
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German (de)
French (fr)
Inventor
Aktiengesellschaft Schering
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Klar, Ulrich
Gay, Jürgen
Skuballa, Werner
Schwede, Wolfgang
Buchmann, Bernd
Bunte, Thomas
Lichtner, Rosemarie
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Application filed by Klar, Ulrich, Gay, Jürgen, Skuballa, Werner, Schwede, Wolfgang, Buchmann, Bernd, Bunte, Thomas, Lichtner, Rosemarie filed Critical Klar, Ulrich
Priority to AU62087/01A priority Critical patent/AU6208701A/en
Publication of WO2001066154A2 publication Critical patent/WO2001066154A2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0453—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole

Definitions

  • the invention relates to radioactively labeled, pharmacologically active epothilone derivatives.
  • Epothilone A H
  • the natural products are not sufficiently stable both chemically and metabolically for drug development. Modifications to the natural product are necessary to eliminate these disadvantages. Such modifications are only possible in a totally synthetic way and presuppose synthesis strategies that enable a broad modification of the natural product.
  • the aim of the structural changes is also to increase the therapeutic range. This can be achieved by improving the selectivity of the action and / or increasing the potency and / or reducing undesirable toxic side effects, as described in Proc. Natl. Acad. Be. USA 1998, 95, 9642-9647 are described.
  • the object of the present invention is to provide new, radioactively labeled epothilone derivatives which are both chemically and metabolically are sufficiently stable and which are comparable or superior to the natural derivatives in terms of their selectivity of the action and / or undesirable toxic side effects and / or their potency.
  • an endocyclic double bond e.g. if R ?, R ⁇ together represent an additional bond
  • a reactive epoxide for example if R 7 , R together represent an oxygen atom
  • R O-PG hydroxyl, in which PG is a protective group, R ⁇ a, R2b are identical or different and are independently hydrogen,
  • R3 C2-C-
  • R 5 hydrogen, Ci-C-in-Al yl, aryl, C7-C-20-aralkyl, halogen, WZ a CH2-CH2, CH2-O or O-CH2 group
  • R 6 hydrogen, CI -CJ Q- Alkyl, aryl, C7-C20-aralkyl, (CH2) S -V, halogen, where s is 1, 2, 3 or 4 and
  • V is O-PG, hydroxyl or halogen, R 7 , R ⁇ je a hydrogen atom, together an additional bond or
  • Oxygen atom, A aryl, Cy ⁇ r j aralkyl, a group R 10 -CH CR 9 -, wherein R 9 is hydrogen, halogen, CN, C-
  • the present invention further relates to compounds of the general formula I 'in which, instead of the substituents mentioned for R 3 in the formula I, there is a C2-C10 alkenyl group which contains 2n-tritium atoms, in which n is 1 or 2.
  • the alkyl groups R a , R 2b , R 3 , R 5 , R 6 , R 9 , R 0 and R 1 1 are straight-chain or branched-chain alkyl groups with 1-20 carbon atoms, such as methyl, ethyl, propyl, isopropyl, Butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl.
  • the alkyl groups R a , R 2b , R 3 , R 5 , R 6 , R 9 , R 10 and R can be perfluorinated or substituted by 1-5 halogen atoms, hydroxyl groups, C-
  • An alkenyl group R 3 is preferably a prop-2-enyl or but-2-enyl group.
  • Aryl radicals R 2a , R 2b , R 5 , R 6 , R 9 , R 10 and A are substituted and unsubstituted carbocyclic or heterocyclic radicals having one or more heteroatoms such as, for example, phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, Oxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl, benzothiazolyl, benzoxazolyl, quinolyl, which can be mono- or polysubstituted by halogen, OH, O-alkyl, CO 2 H, CO 2 -alkyl, -NH 2 , -NO 2 , - N 3 , -CN, C-
  • a substituted aryl radical A this is in particular a 2-methylbenzothiazol-5-yl radical.
  • the aralkyl groups in R 2a , R 2b , R 3 , R 5 , R 6 , R 9 , R 10 and A can contain up to 14 carbon atoms in the ring, preferably 6 to 10 and 1 to 8, preferably 1 to 4 in the alkyl chain Contain atoms.
  • suitable aralkyl radicals are benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl and pyridylpropyl.
  • the rings can be mono- or polysubstituted by halogen, OH, O-alkyl, CO2H, C02-alkyl, - O2, -N3, -CN, -C-C-20-alkyl, C ⁇ , -C20-acyl, C ⁇ -C2r j acyloxy groups.
  • Halogen in R 5 , R6, R 9 and V means fluorine, chlorine, bromine or iodine.
  • Protecting groups PG are the radicals known to the person skilled in the art, such as, for example, alkyl, silyl and acyl radicals. Preferred are easily removable alkyl or silyl radicals from the corresponding alkyl and silyl ethers, such as, for example, methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert.-butyldimethylsilyl, ter-butyldiphene -, Tribenzylsilyl, triisopropylsilyl, benzyl, para-nitrobenzyl, para-methoxybenzyl radical and alkylsulfonyl and arylsulfonyl radicals.
  • acyl residues e.g. Formyl, acetyl, propionyl, isopropionyl, pivalyl, butyryl or benzoyl, which can be substituted with amino and / or hydroxyl groups, into question.
  • the acyl groups PG 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 2a and R 2b is preferably 1, 2, 3 or 4.
  • R 3 has the meaning of [2,3- 3 H] propyl, [2,3- 3 H] -butyl or [3,4- 3 H] -butyl.
  • Another object of the present invention is a process for the preparation of the epothilone derivatives according to the invention of the general formula I or I '.
  • the production of the new epothilone derivatives is based on the reaction of a compound of the general formula II,
  • R 1 , R 2a , R 2b , R 4 , R 5 , R 6 , R 7 , R 8 , A, X, Y, Z and W have the meanings given above and R 3 'is a C2-C ⁇ n-alkenyl , C8-C2f j -Aralkenyl-, C2-C-
  • Alkenyl / alkynyl groups R 3 ' are straight-chain or branched-chain unsaturated alkyl groups with 1-20 carbon atoms, such as ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, heptenyl, heptadienyl, hexenyl, hexadienyl, decenyl, ethynyl, propynyl , Isopropynyl, butynyl, isobutynyl, heptinyl, heptadiynyl, hexynyl, hexadiynyl, decynyl.
  • suitable aralkenyl radicals are phenylethenyl, naphthylethenyl, furylethenyl, thienylethenyl, pyridylpropenyl, phenylethynyl, naphthylethynyl, furylethynyl, thienylethynyl and pyridylpropynyl.
  • the rings can be mono- or polysubstituted by halogen, OH, O-alkyl, CO2H, CO 2 -alkyl, -NO2, -N3, -CN, C- - C20 "alkyl, C-
  • the preparation of compounds of the general formula II is described, for example, in DE 199210861.1 or PCT / IB00 / 00657, the content of which is hereby expressly incorporated by reference.
  • the present invention further relates to medicaments or diagnostic agents which contain at least one epothilone derivative of the general formula I according to the invention.
  • the new compounds of formula I are valuable pharmaceuticals and valuable diagnostic probes for elucidating, for example, mechanisms of action, biochemical, pharmacokinetic and / or pharmacodynamic processes. 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 / diagnosis of diseases in which the influencing of cell division can be therapeutically indicated.
  • Examples include the treatment / diagnosis of malignant tumors, malaria, chronic inflammatory diseases such as psoriasis, the therapy / diagnosis of diseases caused by gram-negative bacteria, and the treatment / diagnosis of diseases of the central and peripheral nervous system, which are based on excitotoxic mechanisms such as the therapy / diagnosis of acute neurodegenerative symptoms, such as those caused by stroke or traumatic brain injuries, the therapy diagnosis of chronic neurodegenerative symptoms including Alzheimer's disease and the therapy / diagnosis of amyothrophic lateral sclerosis.
  • Examples of applications for malignant tumors include therapy / diagnosis of ovarian, stomach, colon, adeno, breast, lung, head and neck carcinomas, malignant melanoma, acute lymphocytic and myelocytic leukemia.
  • the compounds according to the invention can generally be used alone or to achieve additive or synergistic effects in combination with further effects in the respective Therapy / diagnostic areas applicable principles and substance classes can be used.
  • the invention also relates to pharmaceuticals / diagnostics 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 / diagnostics for enteral, percutaneous, parenteral or local application according to known galenical methods. They can be administered in the form of tablets, dragees, 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 auxiliary agents commonly used in galenics, e.g. Cyclodextrins, liposomes, gum arabic, talc, starch, mannitol, methyl cellulose, lactose, surfactants such as tweens or myrj, magnesium stearate, aqueous or non-aqueous carriers, paraffin derivatives, wetting agents, dispersants, emulsifiers, preservatives and flavorings for flavor correction (e.g. essential oils ) are mixed.
  • auxiliary agents commonly used in galenics e.g. Cyclodextrins, liposomes, gum arabic, talc, starch, mannitol, methyl cellulose, lactose, surfactants such as tweens or myrj, magnesium stearate, aqueous or non-aqueous carriers, paraffin derivatives, wetting agents, dispersants, emulsifiers,
  • 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.
  • Each 4x10 6 cells are radiolabelled with 5 ⁇ Ci of the compound from Example 1 and then washed twice with medium and once with PBS.
  • 2 ml of lysis buffer (10 mM Tris HCl pH 7.0, 10 mM NaCl 1, 5 mM MgCl 2 0.2% NP 40) are pipetted onto a perti dish and incubated on ice for 10 min.
  • the cells are carefully scraped off with a rubber policeman and transferred to a Potter jar and homogenized with 30 strokes at 500 rpm.
  • 100 ⁇ l are pipetted off and 4ml of PicoFluor scintillator is added to determine the total activity (total cpm).
  • the rest is transferred to a plastic tube and centrifuged for 20 minutes at 4 ° C and 1000g.
  • 100 ⁇ L of the supernatant are pipetted off (cytosol), the pellet (cores) resuspended in 100 ⁇ l of lysis buffer and 4 ml of PicoFluor scintillator are added.
  • the rest of the supernatant is transferred to an ultracentrifuge tube and centrifuged at 4 ° C and 100000g for 2 hours.
  • 100 ⁇ L of the supernatant (protein) are pipetted off, the pellet (pellet and membranes), resuspended in 100 ⁇ l lysis buffer and mixed with 4ml PicoFluor scintillator.
  • the sample is left to stand for 12 hours, then counted and the cpm corrected to the corresponding total volume.
  • Example 2 In analogy to Example 4, the cellular distribution of the compound from Example 2 is determined.
  • Example 6 In analogy to Example 4, the cellular distribution of the compound from Example 6 is determined.
  • Example 9 (1 S, 3S, 7S, 10R (2E / Z), 11 S, 12S, 16R) -7.11 -dihydroxy-10- [2,3- 3 H] -prop-2-enyl-3- (2-methyl-benzothiazol-5-yl) -8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecan-5,9-dione
  • Example 2 In analogy to Example 4, the cellular distribution of the compound from Example 2 is determined.

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Abstract

The invention relates to novel radioactively labeled pharmacologically effective epothilone derivatives of general formula (I), wherein: R1 represents O-PG and hydroxyl, wherein PG is a protective group; R2a, R2b are the same or different and represent, independent of one another, hydrogen C1-C10 alkyl, aryl, C7-C20 aralkyl or, together, represent a (CH2)m group, wherein m is equal to 1, 2, 3, 4 or 5; R3 represents a C2-C10 alkyl group, a C2-C10 alkenyl group or a C8-C20 aralkyl each containing 2n tritium atoms, wherein n equals 1 or 2; R4 represents O-PG and hydroxyl; R5 represents hydrogen C1-C10 alkyl, aryl, C7-C20 aralkyl and halogen; W-Z represents a CH2-CH2, CH2-O or O-CH2 group; R6 represents hydrogen, C1-C10 alkyl, aryl, C7-C20 aralkyl, (CH2)s-V and halogen, wherein s equals 1, 2, 3 or 4 and V represents O-PG, hydroxyl or halogen; R7, R8 each represent a hydrogen atom and, together, represent an additional bond or an oxygen atom; A represents aryl, C7-C20 aralkyl, and a group R10-CH=C9-, wherein R9 represents hydrogen, halogen, CN, C1-C20 alkyl, aryl, and C7-C20 aralkyl, and R10 represents hydrogen, C1-C20 alkyl-, aryl-, C7-C20 aralkyl, and; X-Y represents an O-C(=O), an O-CH2, a CH2-C(=O), an NR11-C(=O) and an NR11-SO2 group, wherein R11 represents hydrogen and C1-C10 alkyl. The novel compounds of formula (I) are valuable pharmaceuticals and valuable diagnostic probes for elucidating, for example, active mechanisms and biochemical, pharmacocinketic and/or pharmacodynamic processes.

Description

Radioaktiv markierte Epothi Ion-Derivate, Verfahren zu deren Herstellung und ihre biochemische und pharmazeutische Verwendung Radioactive labeled Epothi Ion derivatives, processes for their preparation and their biochemical and pharmaceutical use
Die Erfindung betrifft radioaktiv markierte, pharmakologisch wirksame Epothilon- Derivate.The invention relates to radioactively labeled, pharmacologically active epothilone derivatives.
Von Höfle et al. wird die cytotoxische Wirkung der Naturstoffe Epothilon A (R = Wasserstoff) und Epothilon B (R = Methyl)By Höfle et al. the cytotoxic effects of the natural substances epothilone A (R = hydrogen) and epothilone B (R = methyl)
Figure imgf000003_0001
Epothilon A (R = H), Epothilon B (R=CH3)
Figure imgf000003_0001
Epothilone A (R = H), epothilone B (R = CH 3 )
z.B. in Angew. Chem. 1996, 108, 1671-1673, beschrieben. Wegen der in-vitro- Selektivität gegenüber Brust- und Darmzelllinien und ihrer im Vergleich zu Taxol deutlich höheren Aktivität gegen P-Glycoprotein-bildende, multiresistente Tumorlinien sowie ihre gegenüber Taxol verbesserten physikalischen Eigenschaften, z.B eine um den Faktor 30 höhere Wasserlöslichkeit, ist diese neuartige Strukturklasse für die Entwicklung eines Arzneimittels zur Therapie maligner Tumoren besonders interessant.e.g. in Angew. Chem. 1996, 108, 1671-1673. Because of the in vitro selectivity towards breast and intestinal cell lines and their significantly higher activity against P-glycoprotein-forming, multi-resistant tumor lines compared to Taxol as well as their improved physical properties compared to Taxol, e.g. a 30 times higher water solubility, this is new Structural class of particular interest for the development of a drug for the treatment of malignant tumors.
Die Naturstoffe sind sowohl chemisch als auch metabolisch für eine Arzneimittelentwicklung nicht ausreichend stabil. Zur Beseitigung dieser Nachteile sind Modifikationen an dem Naturstoff nötig. Derartige Modifikationen sind nur auf totalsynthetischem Wege möglich und setzen Synthesestrategien voraus, die eine breite Modifikation des Naturstoffes ermöglichen. Ziel der Strukturveränderungen ist es auch, die therapeutische Breite zu erhöhen. Dies kann durch eine Verbesserung der Selektivität der Wirkung und/oder eine Erhöhung der Wirkstärke und/oder eine Reduktion unerwünschter toxischer Nebenwirkungen, wie sie in Proc. Natl. Acad. Sei. USA 1998, 95, 9642-9647 beschrieben sind, erfolgen.The natural products are not sufficiently stable both chemically and metabolically for drug development. Modifications to the natural product are necessary to eliminate these disadvantages. Such modifications are only possible in a totally synthetic way and presuppose synthesis strategies that enable a broad modification of the natural product. The aim of the structural changes is also to increase the therapeutic range. This can be achieved by improving the selectivity of the action and / or increasing the potency and / or reducing undesirable toxic side effects, as described in Proc. Natl. Acad. Be. USA 1998, 95, 9642-9647 are described.
Die Aufgabe der vorliegenden Erfindung besteht darin, neue, radioaktiv markierte Epothilon-Derivate zur Verfügung zu stellen, die sowohl chemisch als auch metabolisch ausreichend stabil sind und die hinsichtlich ihrer Selektivität der Wirkung und/oder unerwünschter toxischer Nebenwirkungen und/oder ihrer Wirkstärke den natürlichen Derivaten vergleichbar oder überlegen sind.The object of the present invention is to provide new, radioactively labeled epothilone derivatives which are both chemically and metabolically are sufficiently stable and which are comparable or superior to the natural derivatives in terms of their selectivity of the action and / or undesirable toxic side effects and / or their potency.
Es wurde nun überraschenderweise gefunden, daß eine exozyklisch angebrachte Doppelbindung (R3 in I) selektiv in Gegenwart einer endozyklischen Doppelbindung (z. B. wenn R?, R^ gemeinsam eine zusätzliche Bindung darstellen) oder einer weiteren exozyklischen Doppelbindung (z. B. wenn A in I die Bedeutung R10-CH=CR9- besitzt), oder auch in Gegenwart eines reaktiven Epoxides (z. B. wenn R7, R gemeinsam ein Sauerstoffatom darstellen) hydriert bzw. tritiiert werden kann.It has now surprisingly been found that an exocyclically attached double bond (R3 in I) is selective in the presence of an endocyclic double bond (e.g. if R ?, R ^ together represent an additional bond) or a further exocyclic double bond (e.g. if A in I has the meaning R10-CH = CR9-), or also in the presence of a reactive epoxide (for example if R 7 , R together represent an oxygen atom) can be hydrogenated or tritiated.
Die neuen erfindungsgemäßen Epothilon-Derivate sind gekennzeichnet durch die allgemeine Formel I,The new epothilone derivatives according to the invention are characterized by the general formula I,
Figure imgf000004_0001
Figure imgf000004_0001
I, worinI, in which
R O-PG, Hydroxyl, worin PG eine Schutzgruppe ist, R^a, R2b gleich oder verschieden sind und unabhängig voneinander Wasserstoff,R O-PG, hydroxyl, in which PG is a protective group, R ^ a, R2b are identical or different and are independently hydrogen,
C-|-C-|o-Alkyl, Aryl, C7-C2rj-Aralkyl, oder gemeinsam eine -(CH2)m-GruPPe. worin m 1 , 2, 3, 4 oder 5 ist,C- | -C- | o-alkyl, aryl, C7-C2rj-aralkyl, or together a - (CH2) mG ru PP e . where m is 1, 2, 3, 4 or 5,
R3 C2-C-|o- lkyl oder C8-C2fj-Aralkyl, die jeweils 2n-Tritiumatome enthalten, worin n 1 oder 2 ist,R3 C2-C- | o- alkyl or C8-C2f j aralkyl, each of which contains 2n-tritium atoms, in which n is 1 or 2,
R4 O-PG, Hydroxyl,R 4 O-PG, hydroxyl,
R5 Wasserstoff, Ci-C-in-Al yl, Aryl, C7-C-20-Aralkyl, Halogen, W-Z eine CH2-CH2, CH2-O oder O-CH2-Gruppe, R6 Wasserstoff, CI -C-J Q- Alkyl, Aryl, C7-C20-Aralkyl, (CH2)S-V, Halogen, worin s 1 , 2, 3 oder 4 undR 5 hydrogen, Ci-C-in-Al yl, aryl, C7-C-20-aralkyl, halogen, WZ a CH2-CH2, CH2-O or O-CH2 group, R 6 hydrogen, CI -CJ Q- Alkyl, aryl, C7-C20-aralkyl, (CH2) S -V, halogen, where s is 1, 2, 3 or 4 and
V O-PG, Hydroxyl oder Halogen ist, R7, Rδje ein Wasserstoffatom, gemeinsam eine zusätzliche Bindung oder einV is O-PG, hydroxyl or halogen, R 7 , Rδje a hydrogen atom, together an additional bond or
Sauerstoffatom, A Aryl, Cy^rj-Aralkyl, eine Gruppe R10-CH=CR9-, worin R9 Wasserstoff, Halogen, CN, C-|-C20-Alkyl, Aryl, C7-C20-Aralkyl undOxygen atom, A aryl, Cy ^ r j aralkyl, a group R 10 -CH = CR 9 -, wherein R 9 is hydrogen, halogen, CN, C- | -C20 alkyl, aryl, C7-C20 aralkyl and
R10 Wasserstoff, Ci -C20-Alkyl-, Aryl-, C7-C20-Aralkyl- ist, X-Y eine O-C(=O), O-CH2, CH2-C(=O), NR1 1 -C(=O), NR1 1 -SO2 -Gruppe, worin R1 1 Wasserstoff, Cι-C<|n-Alkyl ist, bedeuten.R 1 0 is hydrogen, Ci -C20-alkyl-, aryl-, C7-C20-aralkyl-, XY is an OC (= O), O-CH 2 , CH 2 -C (= O), NR 1 1 -C (= O), NR 1 1 -SO 2 group, in which R 1 1 is hydrogen, -CC <| n-alkyl.
Des weiteren betrifft die vorliegende Erfindung Verbindungen der allgemeinen Formel I', in denen anstelle der in der Formel I für R3 genannten Substituenten eine C2-C10- Alkenylgruppe, die 2n-Tritiumatome enthält, worin n 1 oder 2 ist, steht.The present invention further relates to compounds of the general formula I 'in which, instead of the substituents mentioned for R 3 in the formula I, there is a C2-C10 alkenyl group which contains 2n-tritium atoms, in which n is 1 or 2.
Als Alkylgruppen R a, R2b, R3, R5, R6, R9, R 0 und R1 1 sind gerad- oder verzweigtkettige Alkylgruppen mit 1-20 Kohlenstoffatomen zu betrachten, wie beispielsweise Methyl, Ethyl, Propyl, Isopropyl, Butyl, Isobutyl, tert.-Butyl, Pentyl, Isopentyl, Neopentyl, Heptyl, Hexyl, Decyl.The alkyl groups R a , R 2b , R 3 , R 5 , R 6 , R 9 , R 0 and R 1 1 are straight-chain or branched-chain alkyl groups with 1-20 carbon atoms, such as methyl, ethyl, propyl, isopropyl, Butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl.
Die Alkylgruppen R a, R2b, R3, R5, R6, R9, R10 und R können perfluoriert oder substituiert sein durch 1-5 Halogenatome, Hydroxygruppen, C-|-C4-Alkoxygruppen, Cg- C-i2-Arylgruppen (die durch 1-3 Halogenatome substituiert sein können).The alkyl groups R a , R 2b , R 3 , R 5 , R 6 , R 9 , R 10 and R can be perfluorinated or substituted by 1-5 halogen atoms, hydroxyl groups, C- | -C4-alkoxy groups, Cg-C-i2 -Aryl groups (which can be substituted by 1-3 halogen atoms).
Für eine Alkenylgruppe R3 steht vorzugsweise eine Prop-2-enyl- oder But-2- enylgruppe.An alkenyl group R 3 is preferably a prop-2-enyl or but-2-enyl group.
Als Arylrest R2a, R2b, R5, R6, R9, R10 und A kommen substituierte und unsubstituierte carbocyclische oder heterocyclische Reste mit einem oder mehreren Heteroatomen wie z.B. Phenyl, Naphthyl, Furyl, Thienyl, Pyridyl, Pyrazolyl, Pyrimidinyl, Oxazolyl, Pyridazinyl, Pyrazinyl, Chinolyl, Thiazolyl, Benzothiazolyl, Benzoxazolyl, Chinolyl, die einfach oder mehrfach substituiert sein können durch Halogen, OH, O- Alkyl, CO2H, CO2-Alkyl, -NH2, -NO2, -N3, -CN, C-|-C2o-Alkyl, C-ι-C2o-Acyl, C-|-C2o- Acyloxy-Gruppen, in Frage. Im Falle eines substituierten Arylrestes A ist dies insbesondere ein 2-Methyl- benzothiazol-5-yl-rest. Die Aralkylgruppen in R2a, R2b, R3, R5, R6, R9, R10 und A können im Ring bis 14 C- Atome, bevorzugt 6 bis 10 und in der Alkylkette 1 bis 8, bevorzugt 1 bis 4 Atome enthalten. Als Aralkylreste kommen beispielsweise in Betracht Benzyl, Phenylethyl, Naphthylmethyl, Naphthylethyl, Furylmethyl, Thienylethyl, Pyridylpropyl. Die Ringe können einfach oder mehrfach substituiert sein durch Halogen, OH, O-Alkyl, CO2H, Cθ2-Alkyl, - O2, -N3, -CN, Cι-C-20-Alkyl, Cι,-C20-Acyl, Cι-C2rj-Acyloxy-Gruppen.Aryl radicals R 2a , R 2b , R 5 , R 6 , R 9 , R 10 and A are substituted and unsubstituted carbocyclic or heterocyclic radicals having one or more heteroatoms such as, for example, phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, Oxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl, benzothiazolyl, benzoxazolyl, quinolyl, which can be mono- or polysubstituted by halogen, OH, O-alkyl, CO 2 H, CO 2 -alkyl, -NH 2 , -NO 2 , - N 3 , -CN, C- | -C 2 o-alkyl, C-ι-C 2 o-acyl, C- | -C 2 o-acyloxy groups, in question. In the case of a substituted aryl radical A, this is in particular a 2-methylbenzothiazol-5-yl radical. The aralkyl groups in R 2a , R 2b , R 3 , R 5 , R 6 , R 9 , R 10 and A can contain up to 14 carbon atoms in the ring, preferably 6 to 10 and 1 to 8, preferably 1 to 4 in the alkyl chain Contain atoms. Examples of suitable aralkyl radicals are benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl and pyridylpropyl. The rings can be mono- or polysubstituted by halogen, OH, O-alkyl, CO2H, C02-alkyl, - O2, -N3, -CN, -C-C-20-alkyl, Cι , -C20-acyl, Cι-C2r j acyloxy groups.
Halogen in R5, R6, R9 und V bedeutet Fluor, Chlor, Brom oder lod.Halogen in R 5 , R6, R 9 and V means fluorine, chlorine, bromine or iodine.
Als Schutzgruppen PG kommen die dem Fachmann bekannten Reste wie beispielsweise Alkyl-, Silyl- und Acylreste in Betracht. Bevorzugt sind aus den entsprechenden Alkyl- und Silylethern leicht abspaltbare Alkyl- bzw. Silylreste, wie beispielsweise der Methoxymethyl-, Methoxyethyl, Ethoxyethyl-, Tetrahydropyranyl-, Tetra hydrofuranyl-, Trimethylsilyl-, Triethylsilyl-, tert.-Butyldimethylsilyl-, ter - Butyldiphenylsilyl-, Tribenzylsilyl-, Triisopropylsilyl-, Benzyl, para-Nitrobenzyl-, para- Methoxybenzyl-Rest sowie Alkylsulfonyl- und Arylsulfonylreste. Als Acylreste kommen z.B. Formyl, Acetyl, Propionyl, Isopropionyl, Pivalyl-, Butyryl oder Benzoyl, die mit Amino- und/oder Hydroxygruppen substituiert sein können, in Frage.Protecting groups PG are the radicals known to the person skilled in the art, such as, for example, alkyl, silyl and acyl radicals. Preferred are easily removable alkyl or silyl radicals from the corresponding alkyl and silyl ethers, such as, for example, methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert.-butyldimethylsilyl, ter-butyldiphene -, Tribenzylsilyl, triisopropylsilyl, benzyl, para-nitrobenzyl, para-methoxybenzyl radical and alkylsulfonyl and arylsulfonyl radicals. As acyl residues e.g. Formyl, acetyl, propionyl, isopropionyl, pivalyl, butyryl or benzoyl, which can be substituted with amino and / or hydroxyl groups, into question.
Die Acylgruppen PG können 1 bis 20 Kohlenstoffatome enthalten, wobei Formyl-, Acetyl-, Propionyl-, Isopropionyl und Pivalylgruppen bevorzugt sind.The acyl groups PG can contain 1 to 20 carbon atoms, formyl, acetyl, propionyl, isopropionyl and pivalyl groups being preferred.
Der Index m in der aus R2a und R2b gebildeten Alkylengruppe steht vorzugsweise für 1 , 2, 3 oder 4.The index m in the alkylene group formed from R 2a and R 2b is preferably 1, 2, 3 or 4.
Bei bevorzugten erfindungsgemäßen Epothilon-Derivaten der allgemeinen Formel I hat R3 die Bedeutung von [2,3-3H]-Propyl, [2,3-3H]-Butyl oder [3,4-3H]-Butyl.In preferred inventive epothilone derivatives of general formula I R 3 has the meaning of [2,3- 3 H] propyl, [2,3- 3 H] -butyl or [3,4- 3 H] -butyl.
Die nachstehend genannten Verbindungen sind erfindungsgemäß besonders bevorzugt:The compounds mentioned below are particularly preferred according to the invention:
1. (4S,7R(2RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-methylthiazol- 4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-[2,3-3H]-propyl-cyclohexadec-13-en-2,6- dion 2. (1 S oder R,3S(E),7S,10R(2RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3-3H]- propyl-3-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0]heptadecan-5,9-dion1. (4S, 7R (2RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methylthiazol-4-yl) ethenyl) -1-oxa-5,5,9,13-tetramethyl-7- [2,3- 3 H] propyl-cyclohexadec-13-ene-2,6-dione 2. (1 S or R, 3S (E), 7S, 10R (2RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] - propyl-3- (1-methyl-2- (2-methylthiazol-4-yl) ethenyl) -8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
3. (4S,7R(2RS),8S>9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-fluor-2-(2-methylthiazol-4- yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-[2,3-3H]-propyl-cyclohexadec-13-en-2,6- dion3. (4S, 7R (2RS), 8S > 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-fluoro-2- (2-methylthiazol-4-yl) ethenyl) -1-oxa-5,5,9,13-tetramethyl-7- [2,3- 3 H] -propyl-cyclohexadec-13-ene-2,6-dione
4. (1S oder R)3S(E),7SI10R(2RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3-3H]- propyl-3-(1 -fluor-2-(2-methylthiazol-4-yl)ethenyl)-8,8, 12,16-tetramethyl-4, 17- dioxabicyclo[14.1.0]heptadecan-5,9-dion 5. (4S,7R(2RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-chlor-2-(2-methylthiazol-4- yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-[2,3-3H]-propyl-cyclohexadec-13-en-2,6- dion4. (1S or R ) 3S (E), 7S I 10R (2RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] - propyl-3- ( 1-fluoro-2- (2-methylthiazol-4-yl) ethenyl) -8,8, 12,16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecan-5,9-dione 5. (4S, 7R (2RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-chloro-2- (2-methylthiazol-4-yl) ethenyl) -1-oxa- 5,5,9,13-tetramethyl-7- [2,3- 3 H] -propyl-cyclohexadec-13-ene-2,6-dione
6. (1 S oder R,3S(E),7S,10R(2RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3-3H]- propyl-3-(1 -chlor-2-(2-methylthiazol-4-yl)ethenyl)-8,8, 12, 16-tetramethyl-4, 17- . dioxabicyclo[14.1.0]heptadecan-5,9-dion6. (1 S or R, 3S (E), 7S, 10R (2RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] - propyl-3- (1-chloro-2- (2-methylthiazol-4-yl) ethenyl) -8.8, 12, 16-tetramethyl-4, 17-. dioxabicyclo [14.1.0] heptadecane-5,9-dione
7. (4S,7R(2RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2- pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-[2,3-3H]-propyl-cyclohexadec-13-en- 2,6-dion7. (4S, 7R (2RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-oxa -5,5,9,13-tetramethyl-7- [2,3- 3 H] -propyl-cyclohexadec-13-ene-2,6-dione
8. (1S oder R,3S(E),7S,10R(2RS),11 S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3-3H]- propyl-3-(1 -methyl-2-(2-pyridyl)ethenyl)-8,8, 12,16-tetramethyl-4, 17- dioxabicyclo[14.1.0]heptadecan-5,9-dion8. (1S or R, 3S (E), 7S, 10R (2RS), 11 S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] - propyl-3- (1-methyl-2- (2-pyridyl) ethenyl) -8.8, 12.16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
9. (4S,7R(2RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-fluor-2-(2-pyridyl)ethenyl)- 1-oxa-5,5,9,13-tetramethyl-7-[2,3- H]-propyl-cyclohexadec-13-en-2,6-dion9. (4S, 7R (2RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-fluoro-2- (2-pyridyl) ethenyl) - 1-oxa -5,5,9,13-tetramethyl-7- [2,3-H] propyl-cyclohexadec-13-ene-2,6-dione
10. (1 S oder R,3S(E),7S110R(2RS),11 S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3-3H]- propyl-3-(1 -f luor-2-(2-pyridyl)ethenyl)-8,8, 12, 16-tetramethyl-4, 17- dioxabicyclo[14.1.0]heptadecan-5,9-dion 11. (4S,7R(2RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-chlor-2-(2-pyridyl)ethenyl)- 1-oxa-5,5,9,13-tetramethyl-7-[2,3-3H]-propyl-cyclohexadec-13-en-2,6-dion10. (1 S or R, 3S (E), 7S 1 10R (2RS), 11 S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] - propyl-3 - (1-f luor-2- (2-pyridyl) ethenyl) -8.8, 12, 16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione 11. (4S, 7R (2RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-Dihydroxy-16- (1-chloro-2- (2-pyridyl) ethenyl) - 1-oxa-5,5,9 , 13-tetramethyl-7- [2,3- 3 H] propyl-cyclohexadec-13-ene-2,6-dione
12. (1S oder R,3S(E),7S,10R(2RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3-3H]- propyl-3-(1-chlor-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0]heptadecan-5,9-dion12. (1S or R, 3S (E), 7S, 10R (2RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] - propyl-3- ( 1-chloro-2- (2-pyridyl) ethenyl) -8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
13. (4S,7R(2RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(2-methyl-benzothiazol-5-yl)- 1-oxa-5,5,9,13-tetramethyl-7-[2,3-3H]-propyl-cyclohexadec-13-en-2,6-dion13. (4S, 7R (2RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (2-methyl-benzothiazol-5-yl) - 1-oxa-5, 5,9,13-tetramethyl-7- [2,3- 3 H] propyl-cyclohexadec-13-ene-2,6-dione
14. (1 S oder R,3S(E),7S,10R(2RS),11SI12S,16R oder S)-7,11-Dihydroxy-10-[2,3-3H]- propyl-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0]heptadecan-5,9-dion14. (1 S or R, 3S (E), 7S, 10R (2RS), 11S I 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] - propyl-3- (2-methyl-benzothiazol-5-yl) -8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecan-5,9-dione
15. (4S,7R(2RS),8S,9S, 13E/Z.16S(E))-4,8-Dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1 - oxa-5,5,9,13-tetramethyl-7-[2,3- H]-propyl-cyclohexadec-13-en-2,6-dion 16. (1S oder R,3S(E),7S,10R(2RS),11S>12S,16R oder S)-7,11-Dihydroxy-10-[2,3-3H]- propyl-3-(2-methyl-benzoxazol-5-yl)-8)8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0]heptadecan-5,9-dion15. (4S, 7R (2RS), 8S, 9S, 13E / Z.16S (E)) - 4,8-dihydroxy-16- (2-methyl-benzoxazol-5-yl) -1 - oxa-5, 5,9,13-tetramethyl-7- [2,3-H] propyl-cyclohexadec-13-ene-2,6-dione 16. (1S or R, 3S (E), 7S, 10R (2RS), 11S > 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] - propyl-3- ( 2-methyl-benzoxazol-5-yl) -8 ) 8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecan-5,9-dione
17. (4S,7R(2RS),8S,9S, 13E/Z, 16S(E))-4,8-Dihydroxy-16-(1 -methyl-2-(2-methylthiazol- 4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-[2,3-3H]-propyl-cyclohexadec-13-en-2,6- dion17. (4S, 7R (2RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methylthiazol-4-yl) ethenyl) -1-aza-5,5,9,13-tetramethyl-7- [2,3- 3 H] -propyl-cyclohexadec-13-ene-2,6-dione
18. (1 S oder R,3S(E),7S110R(2RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3-3H]- propyl-3-( 1 -methyl-2-(2-methylthiazol-4-yl)ethenyl)-8,8, 12,16-tetramethyl-4-aza-17- oxabicyclo[14.1.0]heptadecan-5,9-dion 19. (4S,7R(2RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-fluor-2-(2-methylthiazol-4- yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-[2,3-3H]-propyl-cyclohexadec-13-en-2,6- dion 20. (1 S oder R,3S(E),7S,10R(2RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3-3H]- propyl-3-(1-fluor-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17- oxabicyclo[14.1.0]heptadecan-5,9-dion18. (1 S or R, 3S (E), 7S 1 10R (2RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] - propyl-3- (1-methyl-2- (2-methylthiazol-4-yl) ethenyl) -8,8, 12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecane-5,9-dione 19. (4S, 7R (2RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-fluoro-2- (2-methylthiazol-4-yl) ethenyl) -1 -aza-5,5,9,13-tetramethyl-7- [2,3- 3 H] -propyl-cyclohexadec-13-ene-2,6-dione 20. (1 S or R, 3S (E), 7S, 10R (2RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] propyl-3- (1-fluoro-2- (2-methylthiazole-4 -yl) ethenyl) -8,8,12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecane-5,9-dione
21. (4S,7R(2RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-chlor-2-(2-methylthiazol-4- yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-[2,3-3H]-propyl-cyclohexadec-13-en-2,6- dion21. (4S, 7R (2RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-chloro-2- (2-methylthiazol-4-yl) ethenyl) -1-aza-5,5,9,13-tetramethyl-7- [2,3- 3 H] -propyl-cyclohexadec-13-ene-2,6-dione
22. (1 S oder R,3S(E),7S,10R(2RS),11S>12S,16R oder S)-7,11-Dihydroxy-10-[2,3-3H]- propyl-3-(1 -chlor-2-(2-methylthiazol-4-yl)ethenyl)-8,8, 12, 16-tetramethyl-4-aza-17- oxabicyclo[14.1.0]heptadecan-5,9-dion22. (1 S or R, 3S (E), 7S, 10R (2RS), 11S > 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] - propyl-3- (1-chloro-2- (2-methylthiazol-4-yl) ethenyl) -8,8, 12, 16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecane-5,9-dione
23. (4S,7R(2RS),8S,9S,13E/Z,16S(E))-4>8-Dihydroxy-16-(1-methyl-2-(2- pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-[2,3-3H]-propyl-cyclohexadec-13-en- 2,6-dion 24. (1S oder R,3S(E),7S,10R(2RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3-3H]- propyl-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17- oxabicyclo[14.1.0]heptadecan-5,9-dion 25. (4S,7R(2RS),8S,9S,13E/Z)16S(E))-4,8-Dihydroxy-16-(1-fluor-2-(2-pyridyl)ethenyl)-23. (4S, 7R (2RS), 8S, 9S, 13E / Z, 16S (E)) - 4 > 8-dihydroxy-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-aza -5,5,9,13-tetramethyl-7- [2,3- 3 H] -propyl-cyclohexadec-13-ene-2,6-dione 24. (1S or R, 3S (E), 7S, 10R (2RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] propyl-3- (1-methyl-2- (2-pyridyl) ethenyl) -8 , 8,12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecane-5,9-dione 25. (4S, 7R (2RS), 8S, 9S, 13E / Z ) 16S (E) ) -4,8-dihydroxy-16- (1-fluoro-2- (2-pyridyl) ethenyl) -
1-aza-5,5,9,13-tetramethyl-7-[2,3-3H]-propyl-cyclohexadec-13-en-2,6-dion 26. (1 S oder R,3S(E),7S,10R(2RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3-3H]- propyl-3-(1-fluor-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17- oxabicyclo[14.1.0]heptadecan-5,9-dion 27. (4S,7R(2RS),8S,9S,13E/Z)16S(E))-4,8-Dihydroxy-16-(1-chlor-2-(2-pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7- [2,3- 3 H] -propyl-cyclohexadec-13-en-2,6-dione 26. (1 S or R, 3S (E) , 7S, 10R (2RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] propyl-3- (1-fluoro-2- (2-pyridyl) ethenyl) -8,8,12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecan-5,9-dione 27. (4S, 7R (2RS), 8S, 9S, 13E / Z ) 16S (e)) - 4,8-dihydroxy-16- (1-chloro-2- (2-pyridyl) ethenyl) -
1-aza-5,5)9,13-tetramethyl-7-[2,3-3H]-propyl-cyclohexadec-13-en-2,6-dion 28. (1S oder R,3S(E),7S>10R(2RS),11 S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3-3H]- propyl-3-(1-chlor-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17- oxabicyclo[14.1.0]heptadecan-5,9-dion 29. (4S,7R(2RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(2-methyl-benzothiazol-5-yl)- 1-aza-5,5,9,13-tetramethyl-7-[2,3-3H]-propyl-cyclohexadec-13-en-2,6-dion1-aza-5,5 ) 9,13-tetramethyl-7- [2,3- 3 H] -propyl-cyclohexadec-13-ene-2,6-dione 28. (1S or R, 3S (E), 7S > 10R (2RS), 11 S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] propyl-3- (1-chloro-2- (2-pyridyl) ethenyl) -8,8,12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecane-5,9-dione 29. (4S, 7R (2RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (2-methyl-benzothiazol-5-yl) - 1-aza-5, 5,9,13-tetramethyl-7- [2,3- 3 H] propyl-cyclohexadec-13-ene-2,6-dione
30. (1 S oder R,3S(E),7S,10R(2RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3-3H]- propyl-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17- oxabicyclo[14.1.0]heptadecan-5,9-dion30. (1 S or R, 3S (E), 7S, 10R (2RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] - propyl-3- (2-methyl-benzothiazol-5-yl) -8,8,12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecan-5,9-dione
31. (4S,7R(2RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1- aza-5,5,9,13-tetramethyl-7-[2,3-3H]-propyl-cyclohexadec-13-en-2,6-dion31. (4S, 7R (2RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (2-methyl-benzoxazol-5-yl) -1- aza-5, 5,9,13-tetramethyl-7- [2,3- 3 H] propyl-cyclohexadec-13-ene-2,6-dione
32. (1 S oder R,3S(E),7S,10R(2RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3-3H]- propyl-3-(2-methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17- oxabicyclo[14.1.0]heptadecan-5,9-dion32. (1 S or R, 3S (E), 7S, 10R (2RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] - propyl-3- (2-methyl-benzoxazol-5-yl) -8,8,12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecan-5,9-dione
33. (4S,7R(3RS),8S,9S, 13E/Z, 16S(E))-4,8-Dihydroxy-16-(1 -methyl-2-(2-methylthiazol- 4-yl)ethenyl)-1-oxa-5, 5,9,13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13-en-2,6- dion33. (4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methylthiazol-4-yl) ethenyl) -1-oxa-5, 5,9,13-tetramethyl-7- [3,4- 3 H] -butylcyclohexadec-13-ene-2,6-dione
34. (1 S oder R13S(E),7S,10R(3RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[3,4-3H]- butyl-3-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0]heptadecan-5,9-dion34. (1 S or R 1 3S (E), 7S, 10R (3RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [3,4- 3 H] - butyl-3- (1-methyl-2- (2-methylthiazol-4-yl) ethenyl) -8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
35. (4S,7R(3RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-fluor-2-(2-methylthiazol-4- yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13-en-2,6-dion35. (4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-fluoro-2- (2-methylthiazol-4-yl) ethenyl) -1-oxa-5,5,9,13-tetramethyl-7- [3,4- 3 H] -butylcyclohexadec-13-ene-2,6-dione
36. (1S oder R,3S(E),7S,10R(3RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[3,4-3H]- butyl-3-(1-fluor-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0]heptadecan-5,9-dion36. (1S or R, 3S (E), 7S, 10R (3RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [3,4- 3 H] - butyl-3- ( 1-fluoro-2- (2-methylthiazol-4-yl) ethenyl) -8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
37. (4S,7R(3RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-chlor-2-(2-methylthiazol-4- yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13-en-2,6-dion37. (4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-chloro-2- (2-methylthiazol-4-yl) ethenyl) -1-oxa-5,5,9,13-tetramethyl-7- [3,4- 3 H] -butylcyclohexadec-13-ene-2,6-dione
38. (1S oder R,3S(E),7S,10R(3RS)>11 S,12S,16R oder S)-7,11-Dihydroxy-10-[3,4-3H]- butyl-3-(1-chlor-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0]heptadecan-5,9-dion38. (1S or R, 3S (E), 7S, 10R (3RS) > 11 S, 12S, 16R or S) -7,11-dihydroxy-10- [3,4- 3 H] - butyl-3- (1-chloro-2- (2-methylthiazol-4-yl) ethenyl) -8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecan-5,9-dione
39. (4S,7R(3RS),8S>9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2- pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13-en- 2,6-dion 40. (1 S oder R,3S(E),7S,10R(3RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[3,4-3H]- butyl-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0]heptadecan-5,9-dion 41. (4S,7R(3RS),8S,9S, 13E/Z, 16S(E))-4,8-Dihydroxy-16-(1 -fluor-2-(2-pyridyl)ethenyl)-39. (4S, 7R (3RS), 8S > 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-oxa -5,5,9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-ene-2,6-dione 40. (1 S or R, 3S (E), 7S, 10R (3RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [3,4- 3 H] - butyl-3- (1-methyl-2- (2-pyridyl) ethenyl) - 8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione 41. (4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) -4,8-dihydroxy-16- (1-fluoro-2- (2-pyridyl) ethenyl) -
1-oxa-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13-en-2,6-dion 42. (1 S oder R,3S(E),7S,10R(3RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[3,4-3H]- butyl-3-(1 -f luor-2-(2-pyridyl)ethenyl)-8,8, 12,16-tetramethyl-4, 17- dioxabicyclo[14.1.0]heptadecan-5,9-dion 43. (4S,7R(3RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-chlor-2-(2-pyridyl)ethenyl)- 1-oxa-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13-en-2,6-dion1-oxa-5,5,9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-en-2,6-dione 42. (1 S or R, 3S (E) , 7S, 10R (3RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [3,4- 3 H] - butyl-3- (1-fluorine-2- (2-pyridyl ) ethenyl) -8,8, 12,16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione 43. (4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-chloro-2- (2-pyridyl) ethenyl) - 1-oxa -5,5,9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-ene-2,6-dione
44. (1S oder R,3S(E),7S,10R(3RS),11 S>12S,16R oder S)-7,11-Dihydroxy-10-[3,4-3H]- butyl-3-( 1 -chlor-2-(2-pyridyl)ethenyl)-8,8, 12,16-tetramethyl-4, 17- dioxabicyclo[14.1.0]heptadecan-5,9-dion44. (1S or R, 3S (E), 7S, 10R (3RS), 11S > 12S, 16R or S) -7,11-dihydroxy-10- [3,4- 3 H] - butyl-3- (1-chloro-2- (2-pyridyl) ethenyl) -8.8, 12.16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
45. (4S,7R(3RS)>8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(2-methyl-benzothiazol-5-yl)- 1-oxa-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13-en-2,6-dion45. (4S, 7R (3RS) > 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (2-methyl-benzothiazol-5-yl) - 1-oxa-5, 5,9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-ene-2,6-dione
46. (1S oder R,3S(E),7S,10R(3RS),11 S,12S,16R oder S)-7,11-Dihydroxy-10-[3,4-3H]- butyl-3-(2-methyl-benzothiazol-5-yl)-8,8, 12,16-tetramethyl-4, 17- dioxabicyclo[14.1.0]heptadecan-5,9-dion46. (1S or R, 3S (E), 7S, 10R (3RS), 11 S, 12S, 16R or S) -7,11-dihydroxy-10- [3,4- 3 H] - butyl-3- (2-methyl-benzothiazol-5-yl) -8,8, 12,16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecan-5,9-dione
47. (4S,7R(3RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1- oxa-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13-en-2,6-dion47. (4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (2-methyl-benzoxazol-5-yl) -1-oxa-5, 5,9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-ene-2,6-dione
48. (1 S oder R,3S(E),7S,10R(3RS),11 S,12S,16R oder S)-7,11-Dihydroxy-10-[3,4-3H]- butyl-3-(2-methyl-benzoxazol-5-yl)-8,8, 12,16-tetramethyl-4, 17- dioxabicyclo[14.1.0]heptadecan-5,9-dion48. (1 S or R, 3S (E), 7S, 10R (3RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [3,4- 3 H] - butyl-3 - (2-methyl-benzoxazol-5-yl) -8.8, 12,16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecan-5,9-dione
49. (4S,7R(3RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-methylthiazol- 4-yl)ethenyl)-1 -aza-5,5,9, 13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13-en-2,6- dion49. (4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methylthiazol-4-yl) ethenyl) -1-Aza-5,5,9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-ene-2,6-dione
50. (1 S oder R,3S(E),7S,10R(3RS),11 S,12SI16R oder S)-7,11-Dihydroxy-10-[3,4-3H]- butyl-3-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17- oxabicyclo[14.1.0]heptadecan-5,9-dion 51. (4S,7R(3RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-fluor-2-(2-methylthiazol-4- yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13-en-2,6-dion50. (1 S or R, 3S (E), 7S, 10R (3RS), 11 S, 12S I 16R or S) -7,11-dihydroxy-10- [3,4- 3 H] - butyl-3 - (1-methyl-2- (2-methylthiazol-4-yl) ethenyl) -8,8,12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecane-5,9-dione 51 . (4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-fluoro-2- (2-methylthiazol-4-yl) ethenyl) - 1-aza-5,5,9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-ene-2,6-dione
52. (1 S oder R,3S(E),7S,10R(3RS),11SI12S,16R oder S)-7,11-Dihydroxy-10-[3,4-3H]- butyl-3-(1-fluor-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17- oxabicyclo[14.1.0]heptadecan-5,9-dion52. (1 S or R, 3S (E), 7S, 10R (3RS), 11S I 12S, 16R or S) -7,11-dihydroxy-10- [3,4- 3 H] - butyl-3- (1-fluoro-2- (2-methylthiazol-4-yl) ethenyl) -8,8,12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecane-5,9-dione
53. (4S,7R(3RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-chlor-2-(2-methylthiazol-4- yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13-en-2,6-dion53. (4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-chloro-2- (2-methylthiazol-4-yl) ethenyl) -1-aza-5,5,9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-ene-2,6-dione
54. (1S oder R>3S(E),7S,10R(3RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[3,4-3H]- butyl-3-(1-chlor-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17- oxabicyclo[14.1.0]heptadecan-5,9-dion54. (1S or R > 3S (E), 7S, 10R (3RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [3,4- 3 H] - butyl-3- ( 1-chloro-2- (2-methylthiazol-4-yl) ethenyl) -8,8,12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecane-5,9-dione
55. (4S,7R(3RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2- pyridyl)ethenyl)-1-aza-5,5l9,13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13-en- 2,6-dion 56. (1S oder R,3S(E),7S,10R(3RS)>11S,12SI16R oder S)-7,11-Dihydroxy-10-[3,4-3H]- butyl-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17- oxabicyclo[14.1.0]heptadecan-5,9-dion 57. (4S,7R(3RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-fluor-2-(2-pyridyl)ethenyl)- 1-aza-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13-en-2,6-dion55. (4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-aza -5.5 l of 9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-ene-2,6-dione 56. (1S or R, 3S (E), 7S, 10R (3RS)> 11S, 12S 16R I or S) -7,11-dihydroxy-10- [3,4- 3 H] - butyl-3- (1-methyl-2- (2-pyridyl) ethenyl) -8 , 8,12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecane-5,9-dione 57. (4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-fluoro-2- (2-pyridyl) ethenyl) - 1-aza -5,5,9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-ene-2,6-dione
58. (1 S oder R,3S(E)>7S,10R(3RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[3,4-3H]- butyl-3-(1 -f luor-2-(2-pyridyl)ethenyl)-8,8, 12,16-tetramethyl-4-aza-17- oxabicyclo[14.1.0]heptadecan-5,9-dion58. (1 S or R, 3S (E) > 7S, 10R (3RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [3,4- 3 H] - butyl-3- (1-f luor-2- (2-pyridyl) ethenyl) -8.8, 12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecane-5,9-dione
59. (4S,7R(3RS),8S,9S, 13E/Z, 16S(E))-4,8-Dihydroxy-16-(1 -chlor-2-(2-pyridyl)ethenyl)- 1-aza-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13-en-2,6-dion59. (4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-chloro-2- (2-pyridyl) ethenyl) - 1-aza -5,5,9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-ene-2,6-dione
60. (1S oder R,3S(E),7S,10R(3RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[3,4-3H]- butyl-3-(1-chlor-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17- oxabicyclo[14.1.0]heptadecan-5,9-dion60. (1S or R, 3S (E), 7S, 10R (3RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [3,4- 3 H] - butyl-3- ( 1-chloro-2- (2-pyridyl) ethenyl) -8,8,12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecane-5,9-dione
61. (4S,7R(3RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(2-methyl-benzothiazol-5-yl)- 1-aza-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13-en-2,6-dion61. (4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (2-methyl-benzothiazol-5-yl) - 1-aza-5, 5,9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-ene-2,6-dione
62. (1S oder R,3S(E),7S,10R(3RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[3,4-3H]- butyl-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17- oxabicyclo[14.1.0]heptadecan-5,9-dion62. (1S or R, 3S (E), 7S, 10R (3RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [3,4- 3 H] - butyl-3- ( 2-methyl-benzothiazol-5-yl) -8,8,12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecan-5,9-dione
63. (4S,7R(3RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(2-methyl-benzoxazol-5-yl)-1- aza-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13-en-2,6-dion63. (4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (2-methyl-benzoxazol-5-yl) -1- aza-5, 5,9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-ene-2,6-dione
64. (1S oder R,3S(E),7S,10R(3RS),11S,12S)16R oder S)-7,11-Dihydroxy-10-[3,4-3H]- butyl-3-(2-methyl-benzoxazol-5-yl)-8,8, 12,16-tetramethyl-4-aza-17- oxabicyclo[14.1.0]heptadecan-5,9-dion64. (1S or R, 3S (E), 7S, 10R (3RS), 11S, 12S ) 16R or S) -7,11-dihydroxy-10- [3,4- 3 H] - butyl-3- ( 2-methyl-benzoxazol-5-yl) -8,8, 12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecane-5,9-dione
65. (1 S,3SI7S,10R(2RS),11S,12S,16R)-7,11-Dihydroxy-10-[2,3-3H]-propyl-3-(2-methyl- benzothiazol-5-yl)-8,8, 12, 16-tetramethyl-4, 17-dioxabicyclo[14.1.0]heptadecan-5,9- dion65. (1 S, 3S I 7S, 10R (2RS), 11S, 12S, 16R) -7,11-dihydroxy-10- [2,3- 3 H] -propyl-3- (2-methyl-benzothiazole- 5-yl) -8,8, 12, 16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
66.(1 S,3S,7S,10R(2E/Z),11 S,12S,16R)-7,11-Dihydroxy-10-[2,3-3H]-prop-2-enyl-3-(2- methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0]heptadecan-5,9-dion.66. (1 S, 3S, 7S, 10R (2E / Z), 11 S, 12S, 16R) -7,11-dihydroxy-10- [2,3- 3 H] -prop-2-enyl-3- (2-methyl-benzothiazol-5-yl) -8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecan-5,9-dione.
Ein weiterer Gegenstand der vorliegenden Erfindung ist ein Verfahren zur Herstellung der erfindungsgemäßen Epothilon-Derivate der allgemeinen Formel I bzw. I'. Die Herstellung der neuen Epothilon-Derivate basiert auf der Umsetzung einer Verbindung der allgemeinen Formel II,
Figure imgf000012_0001
Another object of the present invention is a process for the preparation of the epothilone derivatives according to the invention of the general formula I or I '. The production of the new epothilone derivatives is based on the reaction of a compound of the general formula II,
Figure imgf000012_0001
worin R1 , R2a, R2b, R4, R5, R6, R7, R8, A, X, Y, Z und W die oben genannten Bedeutungen haben und R3' eine C2-Cιn-Alkenyl-, C8-C2fj-Aralkenyl-, C2-C-|o-Alkinyl- oder C8-C20-Aralkinyl-Gruppe bedeutet, mit Wasserstoff, der das Tritiumisotop mit einem Anteil von bis zu 100% enthält, zu einer Verbindung der allgemeinen Formel I.wherein R 1 , R 2a , R 2b , R 4 , R 5 , R 6 , R 7 , R 8 , A, X, Y, Z and W have the meanings given above and R 3 'is a C2-Cιn-alkenyl , C8-C2f j -Aralkenyl-, C2-C- | means o-alkynyl or C8-C20-aralkynyl group, with hydrogen, which contains the tritium isotope in a proportion of up to 100%, to a compound of general formula I.
Als Alkenyl-/Alkinyl-Gruppen R3' sind gerad- oder verzweigtkettige ungesättigte Alkylgruppen mit 1-20 Kohlenstoffatomen zu betrachten, wie beispielsweise Ethenyl, Propenyl, Isopropenyl, Butenyl, Isobutenyl, Heptenyl, Heptadienyl, Hexenyl, Hexadienyl, Decenyl, Ethinyl, Propinyl, Isopropinyl, Butinyl, Isobutinyl, Heptinyl, Heptadiinyl, Hexinyl, Hexadiinyl, Decinyl.Alkenyl / alkynyl groups R 3 'are straight-chain or branched-chain unsaturated alkyl groups with 1-20 carbon atoms, such as ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, heptenyl, heptadienyl, hexenyl, hexadienyl, decenyl, ethynyl, propynyl , Isopropynyl, butynyl, isobutynyl, heptinyl, heptadiynyl, hexynyl, hexadiynyl, decynyl.
Die Aralkenyl-/Aralkinyl-Gruppen in R3' können im Ring bis 14 C-Atome, bevorzugt 6 bis 10 und in der Alkenylkette 1 bis 8, bevorzugt 1 bis 4 Atome enthalten. Als Aralkenylreste kommen beispielweise in Betracht Phenylethenyl, Naphthylethenyl, Furylethenyl, Thienylethenyl, Pyridylpropenyl, Phenylethinyl, Naphthylethinyl, Furylethinyl, Thienylethinyl, Pyridylpropinyl. Die Ringe können einfach oder mehrfach substituiert sein durch Halogen, OH, O-Alkyl, CO2H, Cθ2-Alkyl, -NO2, -N3, -CN, C- - C20"Alkyl, C-|-C20- cyl, Cι-C2fj-Acyloxy-Gruppen.The aralkenyl / aralkynyl groups in R 3 'can contain up to 14 carbon atoms in the ring, preferably 6 to 10 and in the alkenyl chain 1 to 8, preferably 1 to 4 atoms. Examples of suitable aralkenyl radicals are phenylethenyl, naphthylethenyl, furylethenyl, thienylethenyl, pyridylpropenyl, phenylethynyl, naphthylethynyl, furylethynyl, thienylethynyl and pyridylpropynyl. The rings can be mono- or polysubstituted by halogen, OH, O-alkyl, CO2H, CO 2 -alkyl, -NO2, -N3, -CN, C- - C20 "alkyl, C- | -C20-cyl, Cι-C2f j acyloxy groups.
Die Herstellung von Verbindungen der allgemeinen Formel II ist beispielsweise in DE 199210861.1 bzw. PCT/IB00/00657 beschrieben auf deren Inhalt hiermit ausdrücklich Bezug genommen wird. Ein weiterer Gegenstand der vorliegenden Erfindung sind Arzneimittel oder Diagnostika, welche mindestens ein erfindungsgemäßes Epothilon-Derivat der allgemeinen Formel I enthalten.The preparation of compounds of the general formula II is described, for example, in DE 199210861.1 or PCT / IB00 / 00657, the content of which is hereby expressly incorporated by reference. The present invention further relates to medicaments or diagnostic agents which contain at least one epothilone derivative of the general formula I according to the invention.
Die neuen Verbindungen der Formel I sind wertvolle Pharmaka und wertvolle diagnostische Sonden zur Aufklärung beispielsweise von Wirkmechanismen, biochemischen, pharmakokinetischen und/oder pharmakodynamischen Abläufen. Sie interagieren mit Tubulin, indem sie gebildete Mikrotubuli stabilisieren und sind somit in der Lage, die Zellteilung phasenspezifisch zu beeinflussen. Dies betrifft vor allem schnell wachsende, neoplastische Zellen, deren Wachstum durch interzelluläre Regelmechanismen weitgehend unbeeinflußt ist. Wirkstoffe dieser Art sind prinzipiell geeignet zur Behandlung / Diagnose von Erkrankungen, bei denen die Beeinflussung der Zellteilung therapeutisch indiziert sein kann.The new compounds of formula I are valuable pharmaceuticals and valuable diagnostic probes for elucidating, for example, mechanisms of action, biochemical, pharmacokinetic and / or pharmacodynamic processes. 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 / diagnosis of diseases in which the influencing of cell division can be therapeutically indicated.
Exemplarisch genannt seien hier die Behandlung / Diagnose maligner Tumoren, der Malaria, chronischer entzündlicher Erkrankungen wie beispielsweise der Psoriasis, die Therapie / Diagnose von Erkrankungen welche durch gram-negative Bakterien verursacht sind, sowie die Behandlung / Diagnose von Erkrankungen des zentralen und peripheren Nervensystems, die auf exzitotoxischen Mechanismen beruhen wie z.B. die Therapie / Diagnose akuter neurodegenerativer Erscheinungen, wie sie beispielsweise durch Schlaganfall oder traumatische Hirnverletzungen entstehen, die Therapie Diagnose chronischer neurodegenerativer Erscheinungen einschließlich des Morbus Alzheimer sowie die Therapie / Diagnose der amyothrophen Lateralsklerose.Examples include the treatment / diagnosis of malignant tumors, malaria, chronic inflammatory diseases such as psoriasis, the therapy / diagnosis of diseases caused by gram-negative bacteria, and the treatment / diagnosis of diseases of the central and peripheral nervous system, which are based on excitotoxic mechanisms such as the therapy / diagnosis of acute neurodegenerative symptoms, such as those caused by stroke or traumatic brain injuries, the therapy diagnosis of chronic neurodegenerative symptoms including Alzheimer's disease and the therapy / diagnosis of amyothrophic lateral sclerosis.
Als Anwendungsbereich für maligne Tumoren seien beispielsweise genannt die Therapie / Diagnose von Ovarial-, Magen-, Colon-, Adeno-, Brust-, Lungen-, Kopf- und Nacken-Karzinomen, dem malignen Melanom, der akuten lymphozytären und myelocytären Leukämie.Examples of applications for malignant tumors include therapy / diagnosis of ovarian, stomach, colon, adeno, breast, lung, head and neck carcinomas, malignant melanoma, acute lymphocytic and myelocytic leukemia.
Zur Vermeidung unkontrollierter Zellwucherungen an sowie der besseren Verträglichkeit von medizinischen Implantaten lassen sie sich prinzipiell in die hierfür verwendeten polymeren Materialien auf- bzw. einbringen. Die erfindungsgemäßen Verbindungen können alleine oder zur Erzielung additiver oder synergistischer Wirkungen in Kombination mit weiteren in der Therapie / Diagnose anwendbaren Prinzipien und Substanzklassen verwendet werden.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 substance classes applicable in therapy / diagnosis.
Die erfindungsgemäßen Verbindungen können generell alleine oder zur Erzielung additiver oder synergistischer Wirkungen in Kombination mit weiteren in den jeweiligen Therapie- / Diagnosegebieten anwendbaren Prinzipien und Substanzklassen verwendet werden.The compounds according to the invention can generally be used alone or to achieve additive or synergistic effects in combination with further effects in the respective Therapy / diagnostic areas applicable principles and substance classes can be used.
Die Erfindung betrifft auch Arzneimittel / Diagnostika auf Basis der pharmazeutisch verträglichen, d.h. in den verwendeten Dosen nicht toxischen Verbindungen der allgemeinen Formel I, gegebenenfalls zusammen mit den üblichen Hilfs- und Trägerstoffen.The invention also relates to pharmaceuticals / diagnostics 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.
Die erfindungsgemäßen Verbindungen können nach an sich bekannten Methoden der Galenik zu pharmazeutischen Präparaten / Diagnostika für die enterale, percutane, parenterale oder lokale Applikation verarbeitet werden. Sie können in Form von Tabletten, Dragees, Gelkapseln, Granulaten, Suppositorien, Implantaten, injizierbaren sterilen wäßrigen oder öligen Lösungen, Suspensionen oder Emulsionen, Salben, Cremes und Gelen verabreicht werden.The compounds according to the invention can be processed into pharmaceutical preparations / diagnostics for enteral, percutaneous, parenteral or local application according to known galenical methods. They can be administered in the form of tablets, dragees, gel capsules, granules, suppositories, implants, injectable sterile aqueous or oily solutions, suspensions or emulsions, ointments, creams and gels.
Der oder die Wirkstoffe können dabei mit den in der Galenik üblichen Hilfsstoffen wie z.B. Cyclodextrinen, Liposomen, Gummiarabikum, Talk, Stärke, Mannit, Methylcellulose, Laktose, Tensiden wie Tweens oder Myrj, Magnesiumstearat, wäßrigen oder nicht wäßrigen Trägern, Paraffinderivaten, Netz-, Dispergier-, Emulgier-, Konservierungsmitteln und Aromastoffen zur Geschmackskorrektur (z.B. etherischen Ölen) gemischt werden.The active ingredient (s) can be combined with the auxiliary agents commonly used in galenics, e.g. Cyclodextrins, liposomes, gum arabic, talc, starch, mannitol, methyl cellulose, lactose, surfactants such as tweens or myrj, magnesium stearate, aqueous or non-aqueous carriers, paraffin derivatives, wetting agents, dispersants, emulsifiers, preservatives and flavorings for flavor correction (e.g. essential oils ) are mixed.
Die Erfindung betrifft somit auch pharmazeutische Zusammensetzungen, die als Wirkstoff zumindest eine erfindungsgemäße Verbindung enthalten. Eine Dosiseinheit enthält etwa 0,1-100 mg Wirkstoff(e). Die Dosierung der erfindungsgemäßen Verbindungen liegt beim Menschen bei etwa 0,1-1000 mg pro Tag.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.
Die nachfolgenden Beispiele dienen der näheren Erläuterung der Erfindung, ohne sie darauf einschränken zu wollen: Beispiel 1The following examples serve to explain the invention in more detail without wishing to restrict it: example 1
(4S,7R(2RS),8S,9S,13/Z>16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2-methylthiazol-4- yl)ethenyl)-1 -oxa-5,5,9,13-tetramethyl-7-[2,3-3H]-propyl-cyclohexadec-13-en-2,6- dion Die Lösung von 4,0 mg (7,73 μmol) (4S,7R,8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1- methyl-2-(2-methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-(prop-2-en-1-yl)- cyclohexadec-13-en-2,6-dion, das man in Analogie zu dem in DE 199210861.1 beschrieben Verfahren hergestellt hat, in 1 ,5 ml wasserfreiem und entgastem Tetra hydrofu ran versetzt man bei 23°C mit 8 mg Tris-(triphenylphosphin)- rhodium(l)chlorid und rührt 5 Stunden kräftig unter einer Atmosphäre aus Tritiumgas. Nach Filtration engt man ein und reinigt den Rückstand durch HPLC. Isoliert werden 2,4 mg (4,60 μmol, 60%).(4S, 7R (2RS), 8S, 9S, 13 / Z > 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methylthiazol-4-yl) ethenyl) -1 -oxa-5,5,9,13-tetramethyl-7- [2,3- 3 H] -propyl-cyclohexadec-13-en-2,6-dione The solution of 4.0 mg (7.73 μmol) (4S, 7R, 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-methylthiazol-4-yl) ethenyl) -1-oxa- 5,5,9,13-tetramethyl-7- (prop-2-en-1-yl) cyclohexadec-13-en-2,6-dione, which has been prepared analogously to the process described in DE 199210861.1, in 1.5 ml of anhydrous and degassed tetrahydrofuran, 8 mg of tris (triphenylphosphine) rhodium (l) chloride are added at 23 ° C. and the mixture is stirred vigorously for 5 hours under an atmosphere of tritium gas. After filtration, the mixture is concentrated and the residue is purified by HPLC. 2.4 mg (4.60 μmol, 60%) are isolated.
Beispiel 2 (1 S,3S(E),7S,10R(2RS),11 S,12S,16R)-7,11 -Dihydroxy-10-[2,3-3H]-propyl-3-(1 - methyl-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0]heptadecan-5,9-dionExample 2 (1 S, 3S (E), 7S, 10R (2RS), 11 S, 12S, 16R) -7.11 -dihydroxy-10- [2,3- 3 H] -propyl-3- (1 - methyl-2- (2-methylthiazol-4-yl) ethenyl) -8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecan-5,9-dione
In Analogie zu Beispiel 1 setzt man 1 ,0 mg (1 ,87 μmol) (1 S,3S(E),7S,10R,11S,12S,16R)-7,11-Dihydroxy-10-(prop-2-en-1-yl)-3-(1-methyl-2-(2- methylthiazol-4-yl)ethenyl)-8,8, 12,16-tetramethyl-4,17-dioxabicyclo[14.1. Ojheptadecan- 5,9-dion, das man in Analogie zu dem in DE 199210861.1 beschrieben Verfahren hergestellt hat, um und isoliert nach Aufarbeitung und Reinigung 0,81 mg (1 ,5 μmol, 80%) der Titelverbindung. Analogously to Example 1, 1.0 mg (1.87 μmol) (1 S, 3S (E), 7S, 10R, 11S, 12S, 16R) -7,11-dihydroxy-10- (prop-2- en-1-yl) -3- (1-methyl-2- (2-methylthiazol-4-yl) ethenyl) -8.8, 12,16-tetramethyl-4,17-dioxabicyclo [14.1. Ojheptadecan-5,9-dione, which has been prepared in analogy to the process described in DE 199210861.1, um and isolated 0.81 mg (1.5 μmol, 80%) of the title compound after working up and purification.
Beispiel 3Example 3
Spezifikationen der radioaktiv markierten Verbindungen aus Beispiel 1 und 2.Specifications of the radiolabelled compounds from Examples 1 and 2.
Figure imgf000016_0001
Figure imgf000016_0001
Beispiel 4Example 4
Untersuchung zur Zellgängigkeit und Verteilung der radioaktiv markiertenInvestigation of cell mobility and distribution of the radioactively labeled
Verbindung aus Beispiel 1Compound from example 1
Je 4x106 Zellen werden mit 5μCi der Verbindung aus Beispiel 1 radioaktiv markiert und anschließend zweimal mit Medium und einmal mit PBS gewaschen. Es werden 2ml Lysepuffer (10 mM Tris HCI pH 7,0, 10 mM NaCI 1 ,5 mM MgCI2 0,2 % NP 40) auf eine Pertischale pipettiert und 10 Min. auf Eis inkubiert. Die Zellen werden mit einem rubberpoliceman sorgfältig abgekratzt und in ein Pottergefäß überführt und mit 30 Hüben bei 500upm homogenisiert. 100μl werden abpipettiert und mit 4ml PicoFluor Szintillator zur Bestimmung der Gesamtaktivität (Gesamt cpm) versetzt. Der Rest wird in ein Plastikröhrchen überführt und 20 Minuten bei 4°C und 1000g zentifugiert. Vom Überstand werden 100μL abpipettiert (Zytosol), das Pellet (Kerne) in 100μl Lysepuffer resuspendiert und mit je 4ml PicoFluor Szintillator versetzt. Den Rest des Überstandes überführt man in ein Ultrazentrifugenröhrchen und zentrifugiert bei 4°C und 100000g für 2 Stunden. Vom Überstand (Protein) werden 100μL abpipettiert, das Pellet (Pellet und Membranen), in 100μl Lysepuffer resuspendiert und mit je 4ml PicoFluor Szintillator versetzt. Die Probe läßt man für 12 Stunden stehen, zählt anschließend aus und korrigiert die cpm auf das entsprechende Gesamtvolumen.Each 4x10 6 cells are radiolabelled with 5μCi of the compound from Example 1 and then washed twice with medium and once with PBS. 2 ml of lysis buffer (10 mM Tris HCl pH 7.0, 10 mM NaCl 1, 5 mM MgCl 2 0.2% NP 40) are pipetted onto a perti dish and incubated on ice for 10 min. The cells are carefully scraped off with a rubber policeman and transferred to a Potter jar and homogenized with 30 strokes at 500 rpm. 100μl are pipetted off and 4ml of PicoFluor scintillator is added to determine the total activity (total cpm). The rest is transferred to a plastic tube and centrifuged for 20 minutes at 4 ° C and 1000g. 100 μL of the supernatant are pipetted off (cytosol), the pellet (cores) resuspended in 100 μl of lysis buffer and 4 ml of PicoFluor scintillator are added. The rest of the supernatant is transferred to an ultracentrifuge tube and centrifuged at 4 ° C and 100000g for 2 hours. 100μL of the supernatant (protein) are pipetted off, the pellet (pellet and membranes), resuspended in 100μl lysis buffer and mixed with 4ml PicoFluor scintillator. The sample is left to stand for 12 hours, then counted and the cpm corrected to the corresponding total volume.
Verteilung der Gesamtaktivität [cpm] der Verbindung aus Beispiel 1 in der Zelle
Figure imgf000017_0001
Distribution of the total activity [cpm] of the compound from Example 1 in the cell
Figure imgf000017_0001
Relative Verteilung der Aktivität [%] der Verbindung aus Beispiel 1 in der ZelleRelative distribution of the activity [%] of the compound from Example 1 in the cell
Figure imgf000017_0002
Figure imgf000017_0002
Beispiel 5Example 5
Untersuchung zur Zellgängigkeit und Verteilung der radioaktiv markiertenInvestigation of cell mobility and distribution of the radioactively labeled
Verbindung aus Beispiel 2Compound from example 2
In Analogie zu Beispiel 4 bestimmt man die zelluläre Verteilung der Verbindung aus Beispiel 2.In analogy to Example 4, the cellular distribution of the compound from Example 2 is determined.
Verteilung der Gesamtaktivität [cpm] der Verbindung aus Beispiel 2 in der ZelleDistribution of the total activity [cpm] of the compound from Example 2 in the cell
Figure imgf000017_0003
Figure imgf000017_0003
Relative Verteilung der Aktivität [%] der Verbindung aus Beispiel 2 in der ZelleRelative distribution of the activity [%] of the compound from Example 2 in the cell
Figure imgf000017_0004
Beispiel 6
Figure imgf000017_0004
Example 6
(1 S,3S,7S,10R(2RS),11 S,12S.16R)-7,11 -Dihydroxy-10-[2,3-3H]-propyl-3-(2-methyl- benzothiazol-5-yl)-8,8, 12,16-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecan-5,9- dion(1 S, 3S, 7S, 10R (2RS), 11 S, 12S.16R) -7.11 -Dihydroxy-10- [2,3- 3 H] -propyl-3- (2-methyl-benzothiazole-5 -yl) -8.8, 12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
In Analogie zu Beispiel 1 setzt man 1 ,2 mg (2,21 μmol) (1S,3S,7S,10R,11S,12S,16R)- 7,11-Dihydroxy-10-(prop-2-en-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16- tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecan-5,9-dion, das man in Analogie zu dem in DE 199210861.1 beschrieben Verfahren hergestellt hat, um und isoliert nach Aufarbeitung und Reinigung 1 ,16 mg (2,11 μmol, 95%) der Titelverbindung.In analogy to Example 1, 1.2 mg (2.21 μmol) (1S, 3S, 7S, 10R, 11S, 12S, 16R) - 7,11-dihydroxy-10- (prop-2-en-1- yl) -3- (2-methyl-benzothiazol-5-yl) -8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecan-5,9-dione, which is obtained in analogy to has prepared the process described in DE 199210861.1 in order to isolate, after workup and purification, 1.16 mg (2.11 μmol, 95%) of the title compound.
Beispiel 7Example 7
Spezifikationen der radioaktiv markierten Verbindung aus Beispiel 6.Specifications of the radioactively labeled compound from Example 6.
Figure imgf000018_0001
Figure imgf000018_0001
Beispiel 8Example 8
Untersuchung zur Zellgängigkeit und Verteilung der radioaktiv markiertenInvestigation of cell mobility and distribution of the radioactively labeled
Verbindung aus Beispiel 6.Compound from example 6.
In Analogie zu Beispiel 4 bestimmt man die zelluläre Verteilung der Verbindung aus Beispiel 6.In analogy to Example 4, the cellular distribution of the compound from Example 6 is determined.
Verteilung der Gesamtaktivität [cpm] der Verbindung aus Beispiel 6 in der ZelleDistribution of the total activity [cpm] of the compound from Example 6 in the cell
Figure imgf000019_0001
Figure imgf000019_0001
Relative Verteilung der Aktivität [%] der Verbindung aus Beispiel 6 in der ZelleRelative distribution of the activity [%] of the compound from Example 6 in the cell
Figure imgf000019_0002
Figure imgf000019_0002
Beispiel 9 (1 S,3S,7S,10R(2E/Z),11 S,12S,16R)-7,11 -Dihydroxy-10-[2,3-3H]-prop-2-enyl-3-(2- methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0]heptadecan-5,9-dionExample 9 (1 S, 3S, 7S, 10R (2E / Z), 11 S, 12S, 16R) -7.11 -dihydroxy-10- [2,3- 3 H] -prop-2-enyl-3- (2-methyl-benzothiazol-5-yl) -8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecan-5,9-dione
Die Lösung von 5,0 mg (9,2 μmol) (1 S,3S,7S,10R,11 S,12S,16R)-7,11-Dihydroxy-10- (prop-2-in-1-yl)-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0]heptadecan-5,9-dion, das man in Analogie zu dem in DE 199210861.1 beschrieben Verfahren hergestellt hat, in 0,7 ml Ethylacetat versetzt man mit 7 μl Pyridin, einer Microspatelspitze Pd/Ba2SO4 (10%ig) und hydriert unter 1 at Wasserstoff/Tritium-Gas am Schüttelautomaten für 1 ,5 Minuten. Danach hat sich der Katalysator von braun nach schwarz (aktivierte Form) verfärbt. Man hydriert noch eine weitere Minute, verdünnt mit Dichlormethan, filtriert über Celite und engt ein. Restliches Pyridin wird durch Zugabe von Toluol und anschließendem Einengen entfernt. Den Rückstand reinigt man durch HPLC. Isoliert werden 3,7 mg der Titelverbindung (6,8 mmol, 74%). Beispiel 10The solution of 5.0 mg (9.2 μmol) (1 S, 3S, 7S, 10R, 11 S, 12S, 16R) -7,11-dihydroxy-10- (prop-2-in-1-yl) -3- (2-methyl-benzothiazol-5-yl) -8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecan-5,9-dione, which is analogous to that described in DE 199210861.1 has prepared the method, in 0.7 ml of ethyl acetate, 7 μl of pyridine, a micro spatula tip Pd / Ba 2 SO 4 (10%) and hydrogenation under 1 at hydrogen / tritium gas on an automatic shaker for 1.5 minutes , The catalyst then changed color from brown to black (activated form). The mixture is hydrogenated for a further minute, diluted with dichloromethane, filtered through Celite and concentrated. Residual pyridine is removed by adding toluene and then concentrating. The residue is purified by HPLC. 3.7 mg of the title compound (6.8 mmol, 74%) are isolated. Example 10
Spezifikationen der radioaktiv markierten Verbindung aus Beispiel 9.Specifications of the radioactively labeled compound from Example 9.
Figure imgf000020_0001
Figure imgf000020_0001
Beispiel 11Example 11
Untersuchung zur Zellgängigkeit und Verteilung der radioaktiv markiertenInvestigation of cell mobility and distribution of the radioactively labeled
Verbindung aus Beispiel 9.Compound from Example 9.
In Analogie zu Beispiel 4 bestimmt man die zelluläre Verteilung der Verbindung aus Beispiel 2.In analogy to Example 4, the cellular distribution of the compound from Example 2 is determined.
Verteilung der Gesamtaktivität [cpm] der Verbindung aus Beispiel 9 in der ZelleDistribution of the total activity [cpm] of the compound from Example 9 in the cell
Figure imgf000020_0002
Figure imgf000020_0002
Tabelle 8: Relative Verteilung der Aktivität [%] der Verbindung aus Beispiel 9 in der ZelleTable 8: Relative distribution of the activity [%] of the compound from Example 9 in the cell
Figure imgf000020_0003
Figure imgf000020_0003

Claims

PATENTANSPRÜCHE
Epothilon-Derivate der allgemeinen Formel I,Epothilone derivatives of the general formula I,
Figure imgf000021_0001
Figure imgf000021_0001
I, worin R1 O-PG, Hydroxyl, worin PG eine Schutzgruppe ist, R2a, R2 gleich oder verschieden sind und unabhängig voneinander Wasserstoff, C-|-C 1Q- Alkyl, Aryl, C7-C20-Aralkyl, oder gemeinsam eine -(CH2) -Gruppe, worin m 1 , 2, 3, 4 oder 5 ist, R3 C2-C<|rj-Alkyl oder C8-C20-Aral yl, die jeweils 2n-Tritiumatome enthalten, worin n 1 oder 2 ist,I, in which R 1 is O-PG, hydroxyl, in which PG is a protective group, R 2a , R 2 are identical or different and are independently hydrogen, C- | -C 1Q-alkyl, aryl, C7-C20-aralkyl, or together a - (CH2) group, in which m is 1, 2, 3, 4 or 5, R 3 C2-C <| r j -alkyl or C8 -C20 aral yl, each containing 2n tritium atoms, in which n is 1 or 2,
R4 O-PG, Hydroxyl,R 4 O-PG, hydroxyl,
R5 Wasserstoff, C-|-C-|o-Alkyl, Aryl, C7-C20-Aralkyl, Halogen, W-Z eine CH2-CH2, CH2-O oder O-CH2-Gruppe, R6 Wasserstoff, Cι-Cιn-Alkyl, Aryl, C7-C20-Aralkyl, (CH2)S-V, Halogen, worin s 1 , 2, 3 oder 4 undR 5 is hydrogen, C- | -C- | o-alkyl, aryl, C7-C20-aralkyl, halogen, WZ a CH2-CH2, CH2-O or O-CH2 group, R 6 hydrogen, Cι-Cιn-alkyl, aryl, C7-C20-aralkyl, (CH2 ) S -V, halogen, wherein s is 1, 2, 3 or 4 and
V O-PG, Hydroxyl oder Halogen ist,V is O-PG, hydroxyl or halogen,
R7, R3je ein Wasserstoffatom, gemeinsam eine zusätzliche Bindung oder ein Sauerstoffatom, A Aryl, C7-C20- ralkyl, eine Gruppe R10-CH=CR9-, worin R9 Wasserstoff, Halogen, CN, Cι-C2fj-Alkyl, Aryl, C7-C20"Aralkyl undR 7 , R 3 each represent a hydrogen atom, together an additional bond or an oxygen atom, A aryl, C7-C20-ralkyl, a group R 10 -CH = CR 9 -, wherein R 9 is hydrogen, halogen, CN, Cι-C2f j -Alkyl, aryl, C7-C20 "aralkyl and
R10 Wasserstoff, Cι-C20-Alkyl-, Aryl-, C7-C20-Aralkyl- ist, X-Y eine O-C(=O), O-CH2, CH2-C(=O), NR1 1-C(=O), NR1 1-SO2 -Gruppe, worin R1 1 Wasserstoff, C-|-C-jo-Alkyl ist, bedeuten.R 10 is hydrogen, -C-C20-alkyl, aryl, C7-C20-aralkyl-, XY is an OC (= O), O-CH 2 , CH 2 -C (= O), NR 1 1 -C ( = O), NR 1 1 -SO 2 group, in which R 1 1 is hydrogen, C- | -C-jo-alkyl, mean.
2. Epothilon-Derivate gemäß Anspruch 1 , dadurch gekennzeichnet, dass R3 [2,3-3H]-Propyl, [2,3-3H]-Butyl oder [3,4-3H]-Butyl ist.2. epothilone derivatives that R 3 [2,3- 3 H] propyl, [2,3- 3 H] -butyl or [3,4- 3 H] -butyl according to claim 1, characterized.
3. Epothilon-Derivate gemäß Anspruch 1 , nämlich3. epothilone derivatives according to claim 1, namely
(4S,7R(2RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2- methylthiazol-4-yl)ethenyl)-1-oxa-5, 5,9,13-tetramethyl-7-[2,3- H]-propyl- cyclohexadec-13-en-2,6-dion,(4S, 7R (2RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-Dihydroxy-16- (1-methyl-2- (2-methylthiazol-4-yl) ethenyl) -1 -oxa-5, 5,9,13-tetramethyl-7- [2,3-H] -propylcyclohexadec-13-en-2,6-dione,
(1S oder R,3S(E),7S,10R(2RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3- 3H]-propyl-3-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-(1S or R, 3S (E), 7S, 10R (2RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] -propyl-3- (1- methyl-2- (2-methylthiazol-4-yl) ethenyl) -8,8,12,16-tetramethyl-
4,17-dioxabicyclo[14.1.0]heptadecan-5,9-dion,4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione,
(4S,7R(2RS),8S,9S, 13E/Z, 16S(E))-4,8-Dihydroxy-16-(1 -fluor-2-(2-methylthiazol- 4-yl)ethenyl)-1-oxa-5, 5,9,13-tetramethyl-7-[2,3-3H]-propyl-cyclohexadec-13-en- 2,6-dion,(4S, 7R (2RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-fluoro-2- (2-methylthiazol-4-yl) ethenyl) -1 -oxa-5, 5,9,13-tetramethyl-7- [2,3- 3 H] -propyl-cyclohexadec-13-ene-2,6-dione,
(1 S oder R,3S(E),7S,10R(2RS),11 S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3- 3H]-propyl-3-(1-fluor-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0]heptadecan-5,9-dion,(1 S or R, 3S (E), 7S, 10R (2RS), 11 S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] -propyl-3- ( 1-fluoro-2- (2-methylthiazol-4-yl) ethenyl) -8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecan-5,9-dione,
(4S,7R(2RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-chlor-2-(2- methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-[2,3-3H]-propyl- cyclohexadec-13-en-2,6-dion,(4S, 7R (2RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-Dihydroxy-16- (1-chloro-2- (2-methylthiazol-4-yl) ethenyl) -1 -oxa-5,5,9,13-tetramethyl-7- [2,3- 3 H] -propylcyclohexadec-13-en-2,6-dione,
(1S oder R,3S(E),7S,10R(2RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3-(1S or R, 3S (E), 7S, 10R (2RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3-
3H]-propyl-3-(1 -chlor-2-(2-methylthiazol-4-yl)ethenyl)-8,8, 12,16-tetramethyl- 4,17-dioxabicyclo[14.1.0]heptadecan-5,9-dion, 3 H] -propyl-3- (1-chloro-2- (2-methylthiazol-4-yl) ethenyl) -8,8, 12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5 , 9-dione,
(4S,7R(2RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2- pyridyl)ethenyl)-1 -oxa-5,5,9, 13-tetramethyl-7-[2,3-3H]-propyl-cyclohexadec-13- en-2,6-dion, (1S oder R,3S(E),7S,10R(2RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3- 3H]-propyl-3-( 1 -methyl-2-(2-pyridyl)ethenyl)-8,8, 12,16-tetramethyl-4, 17- dioxabicyclo[14.1.0]heptadecan-5,9-dion,(4S, 7R (2RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-oxa-5 , 5,9,13-tetramethyl-7- [2,3- 3 H] -propyl-cyclohexadec-13-en-2,6-dione, (1S or R, 3S (E), 7S, 10R (2RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] -propyl-3- (1 - methyl-2- (2-pyridyl) ethenyl) -8,8, 12,16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione,
(4S,7R(2RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-fluor-2-(2- pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-[2,3-3H]-propyl-cyclohexadec-13- en-2,6-dion,(4S, 7R (2RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-fluoro-2- (2-pyridyl) ethenyl) -1-oxa-5 , 5,9,13-tetramethyl-7- [2,3- 3 H] -propyl-cyclohexadec-13-en-2,6-dione,
(1S oder R,3S(E),7S,10R(2RS),11 S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3- 3H]-propyl-3-( 1 -f luor-2-(2-pyridyl)ethenyl)-8,8, 12,16-tetramethyl-4, 17- dioxabicyclo[14.1.0]heptadecan-5,9-dion,(1S or R, 3S (E), 7S, 10R (2RS), 11 S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] -propyl-3- (1st -f luor-2- (2-pyridyl) ethenyl) -8.8, 12.16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione,
(4S,7R(2RS),8S,9S, 13E/Z, 16S(E))-4,8-Dihydroxy-16-(1 -chlor-2-(2- pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-[2,3-3H]-propyl-cyclohexadec-13- en-2,6-dion,(4S, 7R (2RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-chloro-2- (2-pyridyl) ethenyl) -1-oxa-5 , 5,9,13-tetramethyl-7- [2,3- 3 H] -propyl-cyclohexadec-13-en-2,6-dione,
(1 S oder R,3S(E),7S,10R(2RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3- 3H]-propyl-3-(1-chlor-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0]heptadecan-5,9-dion,(1 S or R, 3S (E), 7S, 10R (2RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] -propyl-3- (1st -chloro-2- (2-pyridyl) ethenyl) -8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione,
(4S,7R(2RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(2-methyl-benzothiazol-5- yl)-1-oxa-5,5,9,13-tetramethyl-7-[2,3-3H]-propyl-cyclohexadec-13-en-2,6-dion,(4S, 7R (2RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (2-methyl-benzothiazol-5-yl) -1-oxa-5,5, 9,13-tetramethyl-7- [2,3- 3 H] -propyl-cyclohexadec-13-ene-2,6-dione,
(1 S oder R,3S(E),7S,10R(2RS),11 S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3- 3H]-propyl-3-(2-methyl-benzothiazol-5-yl)-8,8, 12, 16-tetramethyl-4, 17- dioxabicyclo[14.1.0]heptadecan-5,9-dion,(1 S or R, 3S (E), 7S, 10R (2RS), 11 S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] -propyl-3- ( 2-methyl-benzothiazol-5-yl) -8,8, 12, 16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecan-5,9-dione,
(4S,7R(2RS),8S)9S)13E/Z,16S(E))-4,8-Dihydroxy-16-(2-methyl-benzoxazol-5- yl)-1 -oxa-5,5,9, 13-tetramethyl-7-[2,3-3H]-propyl-cyclohexadec-13-en-2,6-dion,(4S, 7R (2RS), 8S ) 9S ) 13E / Z, 16S (E)) - 4,8-Dihydroxy-16- (2-methyl-benzoxazol-5-yl) -1-oxa-5,5, 9, 13-tetramethyl-7- [2,3- 3 H] -propyl-cyclohexadec-13-ene-2,6-dione,
(1S oder R,3S(E),7S,10R(2RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3- 3H]-propyl-3-(2-methyl-benzoxazol-5-yl)-8,8, 12, 16-tetramethyl-4, 17- dioxabicyclo[14.1.0]heptadecan-5,9-dion,(1S or R, 3S (E), 7S, 10R (2RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] -propyl-3- (2- methyl-benzoxazol-5-yl) -8,8, 12, 16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecan-5,9-dione,
(4S,7R(2RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2- methylthiazol^-y etheny -l-aza-δ.δ.θ.lS-tetramethyl^-^.S-SHJ-propyl- cyclohexadec-13-en-2,6-dion, (1S oder R,3S(E),7S,10R(2RS),11 S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3-(4S, 7R (2RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-Dihydroxy-16- (1-methyl-2- (2-methylthiazole ^ -y etheny -l-aza- δ.δ.θ.lS-tetramethyl ^ - ^. S-SHJ-propyl-cyclohexadec-13-en-2,6-dione, (1S or R, 3S (E), 7S, 10R (2RS), 11 S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3-
3H]-propyl-3-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4- aza-17-oxabicyclo[14.1.0]heptadecan-5,9-dion, 3 H] -propyl-3- (1-methyl-2- (2-methylthiazol-4-yl) ethenyl) -8,8,12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecane -5,9-dione,
(4S,7R(2RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-fluor-2-(2-methylthiazol-(4S, 7R (2 RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-fluoro-2- (2-methylthiazole
4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-[2,3-3H]-propyl-cyclohexadec-13-en- 2,6-dion,4-yl) ethenyl) -1-aza-5,5,9,13-tetramethyl-7- [2,3- 3 H] -propyl-cyclohexadec-13-ene-2,6-dione,
(1S oder R,3S(E),7S,10R(2RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3- 3H]-propyl-3-(1-fluor-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4- aza-17-oxabicyclo[14.1.0]heptadecan-5,9-dion,(1S or R, 3S (E), 7S, 10R (2RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] -propyl-3- (1- fluoro-2- (2-methylthiazol-4-yl) ethenyl) -8,8,12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecan-5,9-dione,
(4S,7R(2RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-chlor-2-(2- methylthiazol-4-yl)ethenyl)-1 -aza-5,5,9, 13-tetramethyl-7-[2,3-3H]-propyl- cyclohexadec-13-en-2,6-dion,(4S, 7R (2RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-Dihydroxy-16- (1-chloro-2- (2-methylthiazol-4-yl) ethenyl) -1 -aza-5,5,9,13-tetramethyl-7- [2,3- 3 H] -propylcyclohexadec-13-ene-2,6-dione,
(1S oder R,3S(E),7S,10R(2RS),11 S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3- 3H]-propyl-3-(1-chlor-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4- aza-17-oxabicyclo[14.1.0]heptadecan-5,9-dion,(1S or R, 3S (E), 7S, 10R (2RS), 11 S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] -propyl-3- (1st -chloro-2- (2-methylthiazol-4-yl) ethenyl) -8,8,12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecan-5,9-dione,
(4S,7R(2RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2- pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-[2,3-3H]-propyl-cyclohexadec-13- en-2,6-dion,(4S, 7R (2RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-aza-5 , 5,9,13-tetramethyl-7- [2,3- 3 H] -propyl-cyclohexadec-13-en-2,6-dione,
(1S oder R,3S(E),7S,10R(2RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3- H]-propyl-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17- oxabicyclo[14.1.0]heptadecan-5,9-dion,(1S or R, 3S (E), 7S, 10R (2RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3-H] -propyl-3- (1-methyl -2- (2-pyridyl) ethenyl) -8,8,12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecane-5,9-dione,
(4S,7R(2RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-fluor-2-(2- pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-[2,3-3H]-propyl-cyclohexadec-13- en-2,6-dion,(4S, 7R (2RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-fluoro-2- (2-pyridyl) ethenyl) -1-aza-5 , 5,9,13-tetramethyl-7- [2,3- 3 H] -propyl-cyclohexadec-13-en-2,6-dione,
(1 S oder R,3S(E),7S,10R(2RS),11 S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3- 3H]-propyl-3-(1-fluor-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17- oxabicyclo[14.1.0]heptadecan-5,9-dion, (4S,7R(2RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-chlor-2-(2- pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-[2,3-3H]-propyl-cyclohexadec-13- en-2,6-dion,(1 S or R, 3S (E), 7S, 10R (2RS), 11 S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] -propyl-3- ( 1-fluoro-2- (2-pyridyl) ethenyl) -8,8,12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecane-5,9-dione, (4S, 7R (2RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-chloro-2- (2-pyridyl) ethenyl) -1-aza-5 , 5,9,13-tetramethyl-7- [2,3- 3 H] -propyl-cyclohexadec-13-en-2,6-dione,
(1S oder R,3S(E),7S,10R(2RS),11 S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3-(1S or R, 3S (E), 7S, 10R (2RS), 11 S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3-
3H]-propyl-3-(1-chlor-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17- oxabicyclo[14.1.0]heptadecan-5,9-dion, 3 H] -propyl-3- (1-chloro-2- (2-pyridyl) ethenyl) -8,8,12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecane-5.9 -dione
(4S,7R(2RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(2-methyl-benzothiazol-5- yl)-1-aza-5,5,9,13-tetramethyl-7-[2,3- H]-propyl-cyclohexadec-13-en-2,6-dion,(4S, 7R (2RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (2-methyl-benzothiazol-5-yl) -1-aza-5,5, 9,13-tetramethyl-7- [2,3-H] -propyl-cyclohexadec-13-ene-2,6-dione,
(1S oder R,3S(E),7S,10R(2RS),11 S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3- 3H]-propyl-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17- oxabicyclo[14.1.0]heptadecan-5,9-dion,(1S or R, 3S (E), 7S, 10R (2RS), 11 S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] -propyl-3- (2nd -methyl-benzothiazol-5-yl) -8,8,12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecan-5,9-dione,
(4S,7R(2RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(2-methyl-benzoxazol-5- yl)-1-aza-5,5,9,13-tetramethyl-7-[2,3-3H]-propyl-cyclohexadec-13-en-2,6-dion,(4S, 7R (2RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (2-methyl-benzoxazol-5-yl) -1-aza-5,5, 9,13-tetramethyl-7- [2,3- 3 H] -propyl-cyclohexadec-13-ene-2,6-dione,
(1S oder R,3S(E),7S,10R(2RS),11 S,12S,16R oder S)-7,11-Dihydroxy-10-[2,3- 3H]-propyl-3-(2-methyl-benzoxazol-5-yl)-8,8, 12, 16-tetramethyl-4-aza-17- oxabicyclo[14.1.0]heptadecan-5,9-dion,(1S or R, 3S (E), 7S, 10R (2RS), 11 S, 12S, 16R or S) -7,11-dihydroxy-10- [2,3- 3 H] -propyl-3- (2nd -methyl-benzoxazol-5-yl) -8,8, 12, 16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecane-5,9-dione,
(4S,7R(3RS),8S,9S,13E/Z, 16S(E))-4,8-Dihydroxy-16-(1 -methyl-2-(2- methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl- cyclohexadec-13-en-2,6-dion,(4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-Dihydroxy-16- (1-methyl-2- (2-methylthiazol-4-yl) ethenyl) -1 -oxa-5,5,9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-en-2,6-dione,
(1S oder R,3S(E),7S,10R(3RS),11 S,12S,16R oder S)-7,11-Dihydroxy-10-[3,4- 3H]-butyl-3-(1-methyl-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl- 4,17-dioxabicyclo[14.1.0]heptadecan-5,9-dion,(1S or R, 3S (E), 7S, 10R (3RS), 11 S, 12S, 16R or S) -7,11-dihydroxy-10- [3,4- 3 H] -butyl-3- (1st -methyl-2- (2-methylthiazol-4-yl) ethenyl) -8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecan-5,9-dione,
(4S,7R(3RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-fluor-2-(2-methylthiazol- 4-yl)ethenyl)-1 -oxa-5,5,9, 13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13-en- 2,6-dion,(4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-fluoro-2- (2-methylthiazol-4-yl) ethenyl) -1 -oxa-5,5,9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-ene-2,6-dione,
(1S oder R,3S(E),7S,10R(3RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[3,4-(1S or R, 3S (E), 7S, 10R (3RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [3,4-
3H]-butyl-3-(1-fluor-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0]heptadecan-5,9-dion, (4S,7R(3RS),8S,9S, 13E/Z.16S(E))-4,8-Dihydroxy-16-(1 -chlor-2-(2- methylthiazol-4-yl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl- cyclohexadec-13-en-2,6-dion, 3 H] -butyl-3- (1-fluoro-2- (2-methylthiazol-4-yl) ethenyl) -8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5 , 9-dione, (4S, 7R (3RS), 8S, 9S, 13E / Z.16S (E)) - 4,8-Dihydroxy-16- (1-chloro-2- (2-methylthiazol-4-yl) ethenyl) -1 -oxa-5,5,9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-en-2,6-dione,
(1S oder R,3S(E),7S,10R(3RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[3,4-(1S or R, 3S (E), 7S, 10R (3RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [3,4-
3H]-butyl-3-( 1 -chlor-2-(2-methylthiazol-4-yl)ethenyl)-8,8, 12,16-tetramethyl-4, 17- dioxabicyclo[14.1.0]heptadecan-5,9-dion, 3 H] -butyl-3- (1-chloro-2- (2-methylthiazol-4-yl) ethenyl) -8.8, 12,16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5 , 9-dione,
(4S,7R(3RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2- pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13- en-2,6-dion,(4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-oxa-5 , 5,9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-en-2,6-dione,
(1 S oder R,3S(E),7S,10R(3RS),11 S,12S,16R oder S)-7,11-Dihydroxy-10-[3,4- 3H]-butyl-3-(1-methyl-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0]heptadecan-5,9-dion,(1 S or R, 3S (E), 7S, 10R (3RS), 11 S, 12S, 16R or S) -7,11-dihydroxy-10- [3,4- 3 H] -butyl-3- ( 1-methyl-2- (2-pyridyl) ethenyl) -8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione,
(4S,7R(3RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-fluor-2-(2- pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13- en-2,6-dion,(4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-fluoro-2- (2-pyridyl) ethenyl) -1-oxa-5 , 5,9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-en-2,6-dione,
(1S oder R,3S(E),7S,10R(3RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[3,4-(1S or R, 3S (E), 7S, 10R (3RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [3,4-
3H]-butyl-3-(1-fluor-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0]heptadecan-5,9-dion, 3 H] -butyl-3- (1-fluoro-2- (2-pyridyl) ethenyl) -8,8,12,16-tetramethyl-4,17- dioxabicyclo [14.1.0] heptadecane-5,9-dione .
(4S,7R(3RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-chlor-2-(2- pyridyl)ethenyl)-1-oxa-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13- en-2,6-dion,(4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-Dihydroxy-16- (1-chloro-2- (2-pyridyl) ethenyl) -1-oxa-5 , 5,9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-en-2,6-dione,
(1 S oder R,3S(E),7S,10R(3RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[3,4- 3H]-butyl-3-(1-chlor-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0]heptadecan-5,9-dion,(1 S or R, 3S (E), 7S, 10R (3RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [3,4- 3 H] -butyl-3- (1st -chloro-2- (2-pyridyl) ethenyl) -8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione,
(4S,7R(3RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(2-methyl-benzothiazol-5- yl)-1-oxa-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13-en-2,6-dion,(4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (2-methyl-benzothiazol-5-yl) -1-oxa-5,5, 9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-ene-2,6-dione,
(1 S oder R,3S(E),7S,10R(3RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[3,4- 3H]-butyl-3-(2-methyl-benzothiazol-5-yl)-8,8, 12,16-tetramethyl-4, 17- dioxabicyclo[14.1.0]heptadecan-5,9-dion, (4S,7R(3RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(2-methyl-benzoxazol-5- yl)-1-oxa-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13-en-2,6-dion,(1 S or R, 3S (E), 7S, 10R (3RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [3,4- 3 H] -butyl-3- (2nd -methyl-benzothiazol-5-yl) -8,8, 12,16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecan-5,9-dione, (4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (2-methyl-benzoxazol-5-yl) -1-oxa-5,5, 9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-ene-2,6-dione,
(1 S oder R,3S(E),7S,10R(3RS),11 S,12S,16R oder S)-7,11-Dihydroxy-10-[3,4-(1 S or R, 3S (E), 7S, 10R (3RS), 11 S, 12S, 16R or S) -7,11-dihydroxy-10- [3,4-
3H]-butyl-3-(2-methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4,17- dioxabicyclo[14.1.0]heptadecan-5,9-dion, 3 H] butyl-3- (2-methyl-benzoxazol-5-yl) -8,8,12,16-tetramethyl-4,17-dioxabicyclo [14.1.0] heptadecan-5,9-dione,
(4S,7R(3RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2- methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl- cyclohexadec-13-en-2,6-dion,(4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-Dihydroxy-16- (1-methyl-2- (2-methylthiazol-4-yl) ethenyl) -1 -aza-5,5,9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-en-2,6-dione,
(1S oder R,3S(E),7S,10R(3RS),11 S,12S,16R oder S)-7,11-Dihydroxy-10-[3,4- 3H]-butyl-3-( 1 -methyl-2-(2-methylthiazol-4-yl)ethenyl)-8,8, 12,16-tetramethyl-4- aza-17-oxabicyclo[14.1.0]heptadecan-5,9-dion,(1S or R, 3S (E), 7S, 10R (3RS), 11 S, 12S, 16R or S) -7,11-dihydroxy-10- [3,4- 3 H] -butyl-3- (1st -methyl-2- (2-methylthiazol-4-yl) ethenyl) -8,8, 12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecane-5,9-dione,
(4S,7R(3RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-fluor-2-(2-methylthiazol- 4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13-en- 2,6-dion,(4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-fluoro-2- (2-methylthiazol-4-yl) ethenyl) -1 -aza-5,5,9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-ene-2,6-dione,
(1 S oder R,3S(E),7S,10R(3RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[3,4- 3H]-butyl-3-(1-fluor-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4-aza- 17-oxabicyclo[14.1.0]heptadecan-5,9-dion,(1 S or R, 3S (E), 7S, 10R (3RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [3,4- 3 H] -butyl-3- (1st -fluoro-2- (2-methylthiazol-4-yl) ethenyl) -8,8,12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecane-5,9-dione,
(4S,7R(3RS),8S,9S, 13E/Z, 16S(E))-4,8-Dihydroxy-16-(1 -chlor-2-(2- methylthiazol-4-yl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl- cyclohexadec-13-en-2,6-dion,(4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-Dihydroxy-16- (1-chloro-2- (2-methylthiazol-4-yl) ethenyl) -1 -aza-5,5,9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-en-2,6-dione,
(1S oder R,3S(E),7S,10R(3RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[3,4- 3H]-butyl-3-(1-chlor-2-(2-methylthiazol-4-yl)ethenyl)-8,8,12,16-tetramethyl-4- aza-17-oxabicyclo[14.1.0]heptadecan-5,9-dion,(1S or R, 3S (E), 7S, 10R (3RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [3,4- 3 H] -butyl-3- (1- chloro-2- (2-methylthiazol-4-yl) ethenyl) -8,8,12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecan-5,9-dione,
(4S,7R(3RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-methyl-2-(2- pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13- en-2,6-dion, (1S oder R,3S(E),7S,10R(3RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[3,4- 3H]-butyl-3-( 1 -methyl-2-(2-pyridyl)ethenyl)-8,8, 12,16-tetramethyl-4-aza-17- oxabicyclo[14.1.0]heptadecan-5,9-dion,(4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-methyl-2- (2-pyridyl) ethenyl) -1-aza-5 , 5,9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-en-2,6-dione, (1S or R, 3S (E), 7S, 10R (3RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [3,4- 3 H] -butyl-3- (1 - methyl-2- (2-pyridyl) ethenyl) -8,8, 12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecane-5,9-dione,
(4S,7R(3RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-fluor-2-(2- pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13- en-2,6-dion,(4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-fluoro-2- (2-pyridyl) ethenyl) -1-aza-5 , 5,9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-en-2,6-dione,
(1S oder R,3S(E),7S,10R(3RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[3,4- 3H]-butyl-3-(1-fluor-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17- oxabicyclo[14.1.0]heptadecan-5,9-dion,(1S or R, 3S (E), 7S, 10R (3RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [3,4- 3 H] -butyl-3- (1- fluoro-2- (2-pyridyl) ethenyl) -8,8,12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecane-5,9-dione,
(4S,7R(3RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(1-chlor-2-(2- pyridyl)ethenyl)-1-aza-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13- en-2,6-dion,(4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (1-chloro-2- (2-pyridyl) ethenyl) -1-aza-5 , 5,9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-en-2,6-dione,
(1 S oder R,3S(E),7S,10R(3RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[3,4- 3H]-butyl-3-(1-chlor-2-(2-pyridyl)ethenyl)-8,8,12,16-tetramethyl-4-aza-17- oxabicyclo[14.1.0]heptadecan-5,9-dion,(1 S or R, 3S (E), 7S, 10R (3RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [3,4- 3 H] -butyl-3- (1st -chloro-2- (2-pyridyl) ethenyl) -8,8,12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecane-5,9-dione,
(4S,7R(3RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(2-methyl-benzothiazol-5- yl)-1-aza-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13-en-2,6-dion,(4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (2-methyl-benzothiazol-5-yl) -1-aza-5,5, 9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-ene-2,6-dione,
(1S oder R,3S(E),7S,10R(3RS),11 S,12S,16R oder S)-7,11-Dihydroxy-10-[3,4- 3H]-butyl-3-(2-methyl-benzothiazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17- oxabicyclo[14.1.0]heptadecan-5,9-dion,(1S or R, 3S (E), 7S, 10R (3RS), 11 S, 12S, 16R or S) -7,11-dihydroxy-10- [3,4- 3 H] -butyl-3- (2nd -methyl-benzothiazol-5-yl) -8,8,12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecan-5,9-dione,
(4S,7R(3RS),8S,9S,13E/Z,16S(E))-4,8-Dihydroxy-16-(2-methyl-benzoxazol-5- yl)-1-aza-5,5,9,13-tetramethyl-7-[3,4-3H]-butyl-cyclohexadec-13-en-2,6-dion und(4S, 7R (3RS), 8S, 9S, 13E / Z, 16S (E)) - 4,8-dihydroxy-16- (2-methyl-benzoxazol-5-yl) -1-aza-5,5, 9,13-tetramethyl-7- [3,4- 3 H] -butyl-cyclohexadec-13-ene-2,6-dione and
(1S oder R,3S(E),7S,10R(3RS),11S,12S,16R oder S)-7,11-Dihydroxy-10-[3,4-(1S or R, 3S (E), 7S, 10R (3RS), 11S, 12S, 16R or S) -7,11-dihydroxy-10- [3,4-
3H]-butyl-3-(2-methyl-benzoxazol-5-yl)-8,8,12,16-tetramethyl-4-aza-17- oxabicyclo[14.1.0]heptadecan-5,9-dion. 3 H] butyl-3- (2-methylbenzoxazol-5-yl) -8,8,12,16-tetramethyl-4-aza-17-oxabicyclo [14.1.0] heptadecane-5,9-dione.
4. Epothilon-Derivate der allgemeinen Formel I',
Figure imgf000029_0001
4. epothilone derivatives of the general formula I ',
Figure imgf000029_0001
I, worinI, in which
R1 O-PG, Hydroxyl, worin PG eine Schutzgruppe ist, R2a, R2D gleich oder verschieden sind und unabhängig voneinander Wasserstoff,R 1 O-PG, hydroxyl, in which PG is a protective group, R 2a , R 2D are identical or different and are independently hydrogen,
C-|-C-|o-Alkyl, Aryl, C7-C20-Aralkyl, oder gemeinsam eine -(CH2)m-Gruppe, worin m 1 , 2, 3, 4 oder 5 ist,C- | -C- | o-alkyl, aryl, C7-C20-aralkyl, or together a - (CH2) m group, where m is 1, 2, 3, 4 or 5,
R3 C2-Cιrj-Alkenylgruppe, die 2n-Tritiumatome enthält, worin n 1 oder 2 ist, R4 O-PG, Hydroxyl,R 3 C2-Cιr j alkenyl group containing 2n-tritium atoms, wherein n is 1 or 2, R 4 O-PG, hydroxyl,
R5 Wasserstoff, C<|-Cιo-Alkyl, Aryl, C7-C20-Aralkyl, Halogen,R 5 is hydrogen, C < | -Cιo-alkyl, aryl, C7-C20-aralkyl, halogen,
W-Z eine CH2-CH2, CH2-O oder O-CH2-Gruppe,W-Z is a CH2-CH2, CH2-O or O-CH2 group,
R6 Wasserstoff, C-|-C-ιo-Alkyl, Aryl, C7-C20-Aralkyl, (CH2)SN, Halogen, worin s 1 , 2, 3 oder 4 und V O-PG, Hydroxyl oder Halogen ist,R 6 is hydrogen, C- | -C-ιo-alkyl, aryl, C7-C20-aralkyl, (CH2) S N, halogen, where s is 1, 2, 3 or 4 and V O-PG, hydroxyl or halogen,
R7, R^je ein Wasserstoffatom, gemeinsam eine zusätzliche Bindung oder einR 7 , R ^ each represent a hydrogen atom, together an additional bond or a
Sauerstoffatom, A Aryl, C7-C2rj-Aralkyl, eine Gruppe R10-CH=CR9-, worin R9 Wasserstoff, Halogen, CN, C-|-C-20-Alkyl, Aryl, C-7-C2fj-Aralkyl undOxygen atom, A aryl, C7-C2r j aralkyl, a group R 10 -CH = CR 9 -, wherein R 9 is hydrogen, halogen, CN, C- | -C-20 alkyl, aryl, C-7-C2f j aralkyl and
R10 Wasserstoff, C-|-C20-Alkyl-, Aryl-, C7-C20-Aralkyl- ist, X-Y eine O-C(=O), O-CH2, CH2-C(=O), NR1 1-C(=O), NR1 1-SO2 -Gruppe, worin R^ Wasserstoff, C-|-Cκ)-Alkyl ist, bedeuten.R 10 is hydrogen, C- | -C20-alkyl-, aryl-, C7-C20-aralkyl-, XY is OC (= O), O-CH 2 , CH 2 -C (= O), NR 1 1 - C (= O), NR 1 1 -SO 2 group, wherein R ^ is hydrogen, C- | -Cκ) alkyl.
5. Epothilon-Derivate gemäß Anspruch 4, dadurch gekennzeichnet, dass R3 [2,3-3H]-Prop-2-enyl ist.5. epothilone derivatives according to claim 4, characterized in that R 3 is [2,3- 3 H] -prop-2-enyl.
6. Epothilon-Derivate nach Anspruch 4, nämlich (1 S.3S.7S, 10R(2RS), 11 S, 12S, 16R)-7, 11 -Dihydroxy-10-[2,3-3H]-propyl-3-(2- methyl-benzothiazol-5-yl)-8,8, 12, 16-tetramethyl-4, 17- dioxabicyclo[14.1.0]heptadecan-5,9-dion6. epothilone derivatives according to claim 4, namely (1 p.3S.7S, 10R (2RS), 11 S, 12S, 16R) -7, 11 -dihydroxy-10- [2,3- 3 H] -propyl-3- (2-methyl-benzothiazole-5 -yl) -8.8, 12, 16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione
(1 S,3S,7S,10R(2E/Z),11S,12S,16R)-7,11-Dihydroxy-10-[2,3-3H]-prop-2-enyl-3-(1 S, 3S, 7S, 10R (2E / Z), 11S, 12S, 16R) -7,11-dihydroxy-10- [2,3- 3 H] -prop-2-enyl-3-
(2-methyl-benzothiazol-5-yl)-8,8, 12, 16-tetramethyl-4, 17- dioxabicyclo[14.1.0]heptadecan-5,9-dion(2-methyl-benzothiazol-5-yl) -8,8, 12, 16-tetramethyl-4, 17-dioxabicyclo [14.1.0] heptadecan-5,9-dione
7. Verfahren zur Herstellung von Epothilon-Derivate der allgemeinen Formel I bzw. I', das dadurch gekennzeichnet ist, dass man eine Verbindung der allgemeinen Formel7. A process for the preparation of epothilone derivatives of the general formula I or I ', which is characterized in that a compound of the general formula
Figure imgf000030_0001
Figure imgf000030_0001
IIII
worinwherein
R3' eine C2-C-|o-Al enyl-, C8-C20-Aralkenyl-, C2-Cιrj-Alkinyl- oder C8-C20-Aralkinyl- Gruppe bedeutet undR 3 'is a C2-C- | o-Al enyl, C8-C20-aralkenyl, C2-Cιr j -alkynyl or C8-C20-aralkynyl group means and
R1 , R2a, R2b, R4, R5, R6, R7, R8, A, X, Y, Z und W die in Anspruch 1 genannten Bedeutungen haben,R 1 , R 2a , R 2b , R 4 , R 5 , R 6 , R 7 , R 8 , A, X, Y, Z and W have the meanings given in claim 1,
mit Wasserstoff, der das Tritiumisotop mit einem Anteil von bis zu 100% enthält, zu einer Verbindung der allgemeinen Formel I umsetzt.with hydrogen, which contains the tritium isotope in a proportion of up to 100%, to give a compound of the general formula I.
8. Arzneimittel, gekennzeichnet durch einen Gehalt an einer Verbindung gemäß Anspruch 1 , gegebenenfalls unter Zusatz üblicher Hilfs-, Träger- und Zusatzstoffe. 8. Medicament, characterized by a content of a compound according to claim 1, optionally with the addition of customary auxiliaries, carriers and additives.
9. Diagnostikum, gekennzeichnet durch einen Gehalt an einer Verbindung gemäß Anspruch 1 , gegebenenfalls unter Zusatz üblicher Hilfs-, Träger- und Zusatzstoffe. 9. Diagnostic, characterized by a content of a compound according to claim 1, optionally with the addition of customary auxiliaries, carriers and additives.
PCT/EP2001/002699 2000-03-09 2001-03-09 Radioactively labeled epothilone derivatives, method for the production thereof, and their biochemical and pharmaceutical use WO2001066154A2 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7001916B1 (en) 1999-02-11 2006-02-21 Schering, Ag Epothilon derivatives, method for the production and the use thereof as pharmaceuticals
US7125893B1 (en) 1999-04-30 2006-10-24 Schering Ag 6-alkenyl-, 6-alkinyl- and 6-epoxy-epothilone derivatives, process for their production, and their use in pharmaceutical preparations
USRE41990E1 (en) 1996-12-03 2010-12-07 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE41990E1 (en) 1996-12-03 2010-12-07 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto, analogues and uses thereof
US7001916B1 (en) 1999-02-11 2006-02-21 Schering, Ag Epothilon derivatives, method for the production and the use thereof as pharmaceuticals
US7125893B1 (en) 1999-04-30 2006-10-24 Schering Ag 6-alkenyl-, 6-alkinyl- and 6-epoxy-epothilone derivatives, process for their production, and their use in pharmaceutical preparations
US7700621B2 (en) 1999-04-30 2010-04-20 Bayer Schering Pharma Aktiengesellschaft 6-alkenyl-, 6-alkinyl- and 6-epoxy-epothilone derivatives, process for their production, and their use in pharmaceutical preparations

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