WO2001066154A2 - DERIVES D'EPOTHILONE MARQUES PAR VOIE RADIOACTIVE, PROCEDE PERMETTANT DE LES PREPARER ET LEUR UTILISATION BIOCHIMIQUE ET PHARMACEUTIQUE - Google Patents

DERIVES D'EPOTHILONE MARQUES PAR VOIE RADIOACTIVE, PROCEDE PERMETTANT DE LES PREPARER ET LEUR UTILISATION BIOCHIMIQUE ET PHARMACEUTIQUE 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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WO
WIPO (PCT)
Prior art keywords
dione
dihydroxy
tetramethyl
ethenyl
methyl
Prior art date
Application number
PCT/EP2001/002699
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German (de)
English (en)
Inventor
Aktiengesellschaft Schering
Original Assignee
Klar, Ulrich
Gay, Jürgen
Skuballa, Werner
Schwede, Wolfgang
Buchmann, Bernd
Bunte, Thomas
Lichtner, Rosemarie
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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/fr

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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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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Optics & Photonics (AREA)
  • Physics & Mathematics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux dérivés d'épothilone de formule (I) à effet pharmacologique, marqués par voie radioactive. Dans cette formule, R1 désigne O-PG, hydroxyle, PG étant un groupe protecteur ; R2a et R2b sont identiques ou différents et désignent indépendamment l'un de l'autre hydrogène, alkyle C1-C10, aryle, aralkyle C7-C20, ou conjointement, un groupe (CH2)m, dans lequel m vaut 1,2,3,4 ou 5 ; R3 désigne un groupe alykle C2-C10, un groupe alkényle C2-C10 ou aralkyle C8-C20, qui contiennent chacun des atomes de 2n-tritium, où n vaut 1 ou 2 ; R4 désigne O-PG, hydroxyle ; R5 désigne hydrogène, alkyle C1-C10, aryle, aralkyle C7-C20, halogène ; W-Z désignent un groupe CH2-CH2, CH2-O ou un groupe O-CH2; R6 désigne hydrogène, alkyle C1-C10, aryle, aralkyle C7-C20, (CH2)s-V, halogène, où s vaut 1,2,3 ou 4 et V désigne O-PG, hydroxyle ou halogène ; R7,R8 désignent chacun un atome d'hydrogène, conjointement, une liaison supplémentaire ou un atome d'oxygène ; A désigne aryle, aralkyle C7-C20, un groupe R10-CH=CR9-, où R9 désigne hydrogène, halogène, CN, alkyle C1C20, aryle, aralkyle C7-C20 et R10 désigne hydrogène, alkyle C1-C20, aryle, aralkyle C7-c20; X-Y désignent un groupe O-C(=O), un groupe O-CH2, CH2-C(=O), NR11-C(=O), NR11-SO2, où R11 désigne hydrogène, alkyle C1-C10. Ces nouveaux composés de formule (I) constituent des produits pharmaceutiques précieux et des sondes diagnostiques précieuses s'utilisant dans l'interprétation de mécanismes d'action, de processus biochimiques, pharmacocinétiques et/ou pharmacodynamiques. ,
PCT/EP2001/002699 2000-03-09 2001-03-09 DERIVES D'EPOTHILONE MARQUES PAR VOIE RADIOACTIVE, PROCEDE PERMETTANT DE LES PREPARER ET LEUR UTILISATION BIOCHIMIQUE ET PHARMACEUTIQUE WO2001066154A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU62087/01A AU6208701A (en) 2000-03-09 2001-03-09 Radioactively labeled epothilone derivatives, method for the production thereof, and their biochemical and pharmaceutical use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10013363.020000309 2000-03-09
DE10013363 2000-03-09

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WO2001066154A2 true WO2001066154A2 (fr) 2001-09-13

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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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