WO2000049019A2 - Nouveaux derives d'epothilon, leur procede de production et leur utilisation pharmaceutique - Google Patents

Nouveaux derives d'epothilon, leur procede de production et leur utilisation pharmaceutique Download PDF

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WO2000049019A2
WO2000049019A2 PCT/EP2000/001331 EP0001331W WO0049019A2 WO 2000049019 A2 WO2000049019 A2 WO 2000049019A2 EP 0001331 W EP0001331 W EP 0001331W WO 0049019 A2 WO0049019 A2 WO 0049019A2
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methyl
dione
ethenyl
dihydroxy
thiazolyl
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PCT/EP2000/001331
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WO2000049019A3 (fr
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Ulrich Klar
Wolfgang Schwede
Werner Skuballa
Bernd Buchmann
Michael Schirner
Andreas Menrad
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Schering Aktiengesellschaft
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Publication of WO2000049019A3 publication Critical patent/WO2000049019A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • 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.
  • epothilone A The total synthesis of epothilone A is by Schinzer et al. in Chem. Eur. J. 1996, 2, No. 11, 1477-1482 and in Angew. Chem. 1997, 109, No. 5, pp. 543-544).
  • Epothilone derivatives have already been described by Höfle et aJ. described in WO 97/19086. These derivatives were made from natural epothilone A or B.
  • Another synthesis of epothilone and epothilone derivatives was by Nicolaou et al. in Angew. Chem. 1997, 109, No. 1/2, pp. 170-172.
  • the object of the present invention is to provide new epothilone derivatives which are sufficiently stable both chemically and metabolically for drug development and which have a therapeutic breadth, their selectivity of action and / or undesirable toxic side effects and / or their Potency are superior to natural derivatives.
  • the present invention describes the new epothilone derivatives of the general formula I
  • R3a is hydrogen, C 1 -C 8 alkyl, aryl, C 1 -C 4 aralkyl,
  • R14 hydrogen, OR 1 a, shark, OSO 2 R 14b ,
  • R 3b OPG 1 or R3b_ Rl4a together form a bond
  • R 4 is hydrogen, C «
  • R 5 is hydrogen, C-
  • A represents OR 22 or shark
  • R 22 represents hydrogen or PG 4
  • R6, R 7 each represent a hydrogen atom, together an additional bond or an oxygen atom
  • R 8 represents hydrogen, C-
  • X is an oxygen atom, two alkoxy groups OR 23 , a C2-C ⁇
  • R 23 represents a C 1 -C 20 -alkyl radical
  • R 9 represents hydrogen or a protective group PG X ,
  • R10, R 1 1 are the same or different and represent hydrogen, a C 1 -C 20 -alkyl, aryl, C7-C20 aralkyl radical or R10 and R 1 1 together with the methylene carbon atom together for a 5- to 7-membered carbocyclic ring stand, Y one oxygen atom or two hydrogen atoms, Z one oxygen atom or H / OR 12 , in which
  • R 12 is hydrogen or a protective group PG Z.
  • the presentation of the new epothilone derivatives is based on the linkage of three partial fragments A, B and C. This method is used in the production of other epothilone derivatives which differ from the compounds according to the invention in the section from carbon atom 7 to carbon atom 10 in DE 197 51 200.3, filing date November 13, 1997 and in the corresponding PCT / EP98 / 05064.
  • the interfaces are as indicated in the general formula I '.
  • A represents a C1-C6 fragment (epothilone counting) of the general formula
  • R1 4 hydrogen, ORl a , shark, OSO 2 R 14b , Rl 3a , Rl 4a hydrogen, S ⁇ 2-alkyl, SO2-A17I, S ⁇ 2-aralkyl or together a - (CH2) 0 group or together a CR 1 5a R 1 5b group, Rl3b 7 Rl4b hydrogen, Ci ⁇ r j alkyl, aryl, C 1 -C 20 aralkyl, Rl 5a ⁇ Rl 5b are the same or different and are hydrogen, CjC iQ alkyl, aryl,
  • Carbonyl groups in A and R 13 are ketalized, converted into an enol ether or reduced, and free acid groups in A in whose salts can be converted with bases.
  • R 3a 'and R5' have the meanings already given for R a and R 5
  • V is an oxygen atom, two alkoxy groups OR 1 7 , a C2-C ⁇
  • H / OR18, R16 ; R18 independently of one another are hydrogen or a protective group PG ⁇ R17, R ⁇ 9 independently of one another are C 1 -C 20 -alkyl.
  • R 3 ' has the meaning already given for R 3 in the general formula I and R 7 ' is a hydrogen atom
  • R 2 0 is a hydrogen atom or a protective group PG 2 R 2 "1 is a hydroxyl group, halogen, a protected hydroxyl group
  • -C « ⁇ o-alkyl or phenyl ) or a phosphine oxide residue P (O) Ph2 (Ph phenyl), U one oxygen atom, two alkoxy groups OR 23 , one C2-C-
  • R 23 represents a C 1 -C 20 -alkyl radical
  • R 9 for hydrogen or a protective group PG 3 , RI O, R " ! 1 are the same or different and for hydrogen, a C-
  • Rl a , Rl b R2a, R 2b R 3a, R 4, R5, R 8 > R 10 > R1 1, R 13b Rl4b_ Rl 5a_ R 15b Rl7 f R19 and R 23 are straight or branched chain alkyl groups with 1 -20 carbon atoms to consider, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl.
  • the alkyl groups Rl, Rl b R 2a , R 2 b, R 3a f R 4, R5_ R8 TR 10 f R1 1, Rl 3b_ Rl4b > Rl 5a ⁇ Rl 5b_ R17_ R19 unc j R23 can be perfluorinated or substituted by 1 -5 Halogen atoms, hydroxyl groups, C ⁇ -C4 alkoxy groups, C6-C12 aryl groups (which can be substituted by 1 -3 halogen atoms).
  • Heteroatoms in the heteroaryl residues can be oxidized; for example, the thiazole ring can be in the form of the N-oxide.
  • the aralkyl groups in Rl a , R " ⁇ R 2a f R 2b ⁇ R 3a _ R 4_ R 5 > R 8 f R 10 t R 11 _ R 13b R 4b , Rl5a and R 15b can contain up to 14 C atoms in the ring, preferably 6 to 10 and in the alkyl chain contain 1 to 8, preferably 1 to 4.
  • aralkyl radicals examples include benzyl, phenylethyl, naphthyimethyl, naphthylethyl, furylmethyl, thienylethyl, pyridylpropyl.
  • the rings can be mono- or polysubstituted by halogen , OH, O-alkyl, CO2H, C ⁇ 2-alkyl, -NO2, -N3, -CN, CiC ⁇ o-alkyl, C ⁇ -C-20-acyl, C ⁇
  • the alkoxy groups contained in X in the general formula I should each contain 1 to 20 carbon atoms, with methoxy, ethoxy, propoxy, isopropoxy and t-butyloxy groups being preferred.
  • Representatives of the protective groups PG are alkyl- and / or aryl-substituted silyl, C-
  • alkyl, silyl and acyl radicals for the protective groups PG are the radicals known to the person skilled in the art.
  • Preferred are easily removable alkyl or silyl residues from the corresponding alkyl and silyl ethers, such as, for example, methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethyisilyl, tert-butyldimethylsilyl, tert.-butyldiphenyldiphenyldiphenyl -, Tribenzylsilyl, triisopropylsilyl, benzyl, para-nitrobenzyl, para-methoxybenzyl radical and alkylsulfonyl and arylsulfonyl radicals.
  • acyl residues e.g. Formyl, acetyl, propionyl, isopropionyl, pivalyl, butyryl or benzoyl, which can be substituted with amino and / or hydroxyl groups, into question.
  • the acyl groups PG X and PG Z in R 9 and R 12 can contain 1 to 20 carbon atoms, formyl, acetyl, propionyl, isopropionyl and pivalyl groups being preferred.
  • the index m in the alkylene group formed from R 1 a and Rl b is preferably 1, 2, 3 or 4.
  • o-alkylene- ⁇ , ⁇ -dioxy group which is possible for X is preferably an ethylene ketal or neopentyl ketal group.
  • Halogen means a fluorine, chlorine, bromine or iodine atom.
  • the compounds mentioned below are preferred according to the invention:
  • the partial fragments (synthesis building blocks) of the general formula A can be prepared as described in DE 197 51 200.3 or the corresponding PCT / EP98 / 05064.
  • the partial fragments B are represented according to scheme 1:
  • the protective groups PG 3 include the protective groups known to the person skilled in the art, such as, for example, methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert.-butyldimethylsilyl, tert.-butyldiphenylsilylsilyl, tribenzylsilyl, tribenzylsilylsilyl, tribenzylsilylsilyl, tribenzylsilylsilyl, tribenzylsilylsilyl and tribenzylsilylsilylsoles -, Benzyl, para-nitrobenzyl, para-methoxybenzyl, formyl, acetyl, 1, 1, 1-trichloroacetyl, propionyl, isopropionyl, pivalyl
  • Preferred radicals are those which can be cleaved reductively or under basic reaction conditions, such as the acetyl, 1, 1, 1 trichloroacetyl, propionyl, isopropionyl, pivalyl, butyryl or benzoyl radical.
  • the acetyl radical is particularly preferred.
  • the reduction of the carbonyl group in B-III can be carried out by the methods known to the person skilled in the art.
  • reducing agents are e.g. Sodium borohydride, diisobutyl aluminum hydride and complex metal hydrides such as Lithium aluminum hydride in question.
  • the free hydroxy group in B-IV is protected by the methods known to the person skilled in the art.
  • the protective groups PG 9 are the protective groups known to the person skilled in the art, as already described above for PG ⁇ in step a (B-II
  • Protective groups which can be cleaved under the action of fluoride such as e.g. the trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl radical.
  • tert-butyldimethylsilyl, the triisopropylsilyl and the tert.-butyldiphenylsilyl radical are particularly preferred.
  • Suitable for saponification are carbonates in alcoholic solution such as potassium carbonate in methanol, aqueous solutions of alkali hydroxides such as lithium hydroxide or sodium hydroxide using organic, water-miscible solvents such as methanol, ethanol, tetrahydrofuran or dioxane.
  • the oxidation of the primary alcohol in B-VI to the aldehyde takes place according to the methods known to the person skilled in the art. Examples include oxidation with manganese dioxide, pyridinium chlorochromate, pyridinium dichromate, chromium trioxide-pyridine complex, oxidation according to Swern or related methods, e.g. using oxalyl chloride in dimethyl sulfoxide, using Dess-Martin periodinane, using nitrogen oxides such as e.g. N-methyl-morpholino-N-oxide in the presence of suitable catalysts such as e.g. Tetrapropylammonium perruthenate in inert solvents. Oxidation according to Swern and with N-methyl-morpholino-N-oxide using tetrapropylammonium perruthenate is preferred.
  • the compound B-VIII is made according to the methods known to those skilled in the art, e.g. implemented in a Wittig or Wittig / Horner reaction or an analog variant.
  • the Wittig and Wittig / Horner reaction is preferred using phosphonium halides of the type
  • the ester B-VIII is reduced to the alcohol B-IX by the methods known to the person skilled in the art.
  • Aluminum hydrides such as e.g. Diisobutyl aluminum hydride or lithium aluminum hydride.
  • the reaction takes place in an inert solvent such as e.g. Toluene.
  • Oxygen of the general formula BX is carried out according to those mentioned under e) Method. Oxidation with manganese dioxide is preferred.
  • the carbonyl group can optionally be converted into a ketal by the processes known to the person skilled in the art (W in the meaning of two alkoxy groups OR ⁇ 9 or a C2 ⁇ Cl ⁇ "alkylene- ⁇ , ⁇ -dioxy group).
  • the oxidation of the alcohol B-Xl to the ketone of the general formula B-Xll takes place according to the process mentioned under e). Oxidation with N-methylmorpholino-N-oxide using tetrapropylammonium perruthenate is preferred.
  • the carbonyl group can optionally be converted into a ketal by the processes known to the person skilled in the art (W in the meaning of two alkoxy groups OR ⁇ 9 or a C2-C-
  • the hydroxyl group in B-IX can be provided with a protective group PG ' O by the processes mentioned under a).
  • a protective group PG ' O Preference is given to silicon-containing protective groups which can be cleaved under acidic reaction conditions or using fluoride, such as, for example, the tetrahydropyranyl, trimethylsilyl, triethylsilyl, tert.-butyldimethylsilyl, tert.-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl radical.
  • the protection group PG 9 introduced under step c) is according to the
  • B-XVI (V in the meaning of oxygen) takes place according to those mentioned under e) Method.
  • Preferred is the use of the chromium trioxide-pyridine complex or the oxidation with N-methyl-morpholino-N-oxide using tetrapropylammonium perruthenate.
  • the carbonyl group can optionally be converted into a ketal by the processes known to the person skilled in the art (V in the meaning of two alkoxy groups OR 19 or one C2-C-
  • the partial fragments (synthesis building blocks) of the general formula C can be prepared as described in DE 197 51 200.3 or in the corresponding PCT / EP98 / 05064.
  • Rl a ', Rlb', R 3a ⁇ R 5 > R 13_ R 14 f Q, E, V and Z have the meanings already mentioned and PG "14 represents a hydrogen atom or a protective group PG, are made from the fragments A and B described above according to that shown in Scheme 2 Procedure received.
  • the compound B in which W has the meaning of an oxygen atom and any additional carbonyl groups present are protected, is alkylated with the enolate of a carbonyl compound of the general formula A.
  • the enolate is formed by the action of strong bases such as e.g. Lithium diisopropylamide, lithium hexamethyldisilazane produced at low temperatures. Partial fragments of the general formula ABC
  • the compound C in which R2 has the meaning of a Wittig salt and any additional carbonyl groups which may be present are protected, is deprotonated by a suitable base, such as, for example, n-butyllithium, lithium diisopropylamide, potassium, tert.-butanolate, sodium or lithium hexamethyldisiiazide, and with a compound AB, in which V has the meaning of an oxygen atom, implemented.
  • Step c (ABC > I):
  • the compounds ABC in which R 13 is a carboxylic acid CO2H and R20 is a hydrogen atom, are added to the compounds of the formula I, in which Y is the Meaning of an oxygen atom, um.
  • the compounds ABC in which R 13 represents a group CH2OH and R20 represents a hydrogen atom, can preferably be used using
  • Triphenylphosphine and azodiesters such as
  • the compounds ABC in which R1 3 represents a group CH2 ⁇ S ⁇ 2Al yl or CH2OSO2A1NI or CH2 ⁇ S ⁇ 2Aral yl and R 0 represents a hydrogen atom, can be deprotonated with suitable bases, for example
  • Free hydroxyl groups in I, A, B, C, AB, ABC can be further functionally modified by etherification or esterification, free carbonyl groups by ketalization, enol ether formation or reduction.
  • the compounds of the formulas B, AB, CB, ABC and I in which GE has a double bond can be converted into further compounds of the formulas B, AB, CB by hydrogenation, deuteration, tritiation, epoxidation, bis-hydroxylation, hydroboration.
  • ABC and I can be transferred according to methods familiar to those skilled in the art for these reaction steps. If R3b is a hydroxy group, this can be eliminated to the diene.
  • the invention relates to all stereoisomers of these compounds and also their mixtures. Biological effects and areas of application of the new derivatives:
  • the new compounds of formula I are valuable pharmaceuticals. They interact with tubulin by stabilizing formed microtubules and are therefore able to influence cell division in a phase-specific manner. This concerns above all fast growing, neoplastic cells, the growth of which is largely unaffected by intercellular control mechanisms.
  • active substances of this type are suitable for the treatment of malignant tumors. Areas of application include the therapy of ovarian, stomach, colon, adeno, breast, lung, head and neck carcinomas, malignant melanoma, acute lymphocytic and myelocytic leukemia.
  • the compounds according to the invention are suitable in principle for anti-angiogenesis therapy and for the treatment of chronic inflammatory diseases such as, for example, psoriasis or arthritis.
  • chronic inflammatory diseases such as, for example, psoriasis or arthritis.
  • they can in principle be applied or incorporated into the polymeric materials used for this.
  • the compounds according to the invention can be used alone or to achieve additive or synergistic effects in combination with other principles and classes of substances which can be used in tumor therapy. Examples include the combination with
  • Platinum complexes such as Cisplatin, carboplatin,
  • Intercalating substances e.g. from the class of anthracyclines such as Doxorubicin or from the class of antrapyrazoles such as e.g. CI-941,
  • Substances interacting with tubulin e.g. from the class of Vinka alkaloids such as Vincristine, vinblastine or from the taxane class such as Taxol, Taxotere or from the macrolide class such as e.g. Rhizoxin or other compounds such as e.g. Colchicine, combretastatin A-4, • DNA topoisomerase inhibitors such as e.g. Camptothecin, etoposide, topotecan, teniposide,
  • Vinka alkaloids such as Vincristine, vinblastine or from the taxane class such as Taxol, Taxotere or from the macrolide class such as e.g. Rhizoxin or other compounds such as e.g. Colchicine, combretastatin A-4, • DNA topoisomerase inhibitors such as e.g. Camptothecin, etoposide, topotecan, teniposide,
  • DNA alkylating compounds such as e.g. Adozelesin, dystamycin A,
  • Inhibitors of growth factors e.g. PDGF, EGF, TGFb, EGF
  • growth factors e.g. PDGF, EGF, TGFb, EGF
  • Somatostatin e.g. Somatostatin, suramin, bombesin antagonists
  • Inhibitors of protein tyrosine kinase or protein kinases A or C such as, for example, erbstatin, genistein, staurosporin, llmofosin, 8-CI-cAMP, Anti-hormones from the class of antigestagens such as mifepristone, onapristone or from the class of anti-estrogens such as tamoxifen or from the class of anti-androgens such as cyproterone acetate,
  • Metastasis inhibiting compounds e.g. from the class of eicosanoids such as PGI2, PGE-
  • Derivatives e.g. Iloprost, Cicaprost, Misoprostol.
  • Inhibitors of oncogenic RAS proteins which influence mitotic signal transduction for example inhibitors of famesyl protein transferase, natural or artificially produced antibodies which are directed against factors or their receptors which promote tumor growth, for example the erbB2 antibody ,
  • the invention also relates to pharmaceuticals based on the pharmaceutically acceptable, i.e. in the doses used, non-toxic compounds of the general formula I, if appropriate together with the customary auxiliaries and carriers.
  • the compounds according to the invention can be processed into pharmaceutical preparations for enteral, percutaneous, parenteral or local application according to known galenical methods. They can be administered in the form of tablets, dragées, gel capsules, granules, suppositories, implants, injectable sterile aqueous or oily solutions, suspensions or emulsions, ointments, creams and gels.
  • the active ingredient (s) can be combined with the auxiliaries commonly used in galenics, e.g.
  • 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.
  • Example 10 Analogously to Example 10, 2.07 g (2.25 mmol) of the compound shown in Example 1 p is reacted at -20 ° C. and, after workup and purification, 783 mg (0.97 mmol, 43%) of the title compound is isolated as colorless oil.
  • Example 1 k Analogously to Example 1 k, 209 mg (255 ⁇ mol) of the compound B shown in Example 1s is reacted and, after workup, 224 mg (max. 255 ⁇ mol) of the title compound is isolated as a crude product, which is reacted further without purification.
  • Example 2a Analogously to Example 1 u, 224 mg (255 ⁇ mol) of the compound shown in Example 2a is reacted and, after workup and purification, 40 mg (58 ⁇ mol, 23%) of the title compound are isolated.

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Abstract

L'invention concerne de nouveaux dérivés d'épothilon correspondant à la formule générale (I), dans laquelle les substituants Y, Z, R?1a, R1b, R2a, R2b¿, G'-G-E-E', R?5, R6, R7, R8, R14¿ et X ont les significations données avec plus de précision dans la description. Ces nouveaux composés interagissent avec la tubuline par le fait qu'ils stabilisent des microtubules formés. Ils peuvent influer sur la division cellulaire de façon spécifique à une phase et ils conviennent pour le traitement de tumeurs malignes, par exemple des carcinomes ovarien, gastrique, du colon, du sein, du poumon, de la tête et du cou, de l'adénocarcinome, du mélanome malin, et de la leucémie lymphocytaire et myélocytaire. Ils peuvent en outre être utilisés pour la thérapie anti-angiogenèse ainsi que pour le traitement de maladies inflammatoires chroniques (psoriasis, arthrite). Pour éviter des proliférations cellulaires non contrôlées et pour améliorer la tolérance d'implants médicaux, ces composés peuvent être appliqués sur des matériaux polymères ou incorporés à ceux-ci. Les composés selon l'invention peuvent être utilisés seuls ou bien, pour l'obtention d'effets additifs ou synergiques, en combinaison avec d'autres principes actifs et classes de substances utilisables dans le traitement des tumeurs.
PCT/EP2000/001331 1999-02-18 2000-02-18 Nouveaux derives d'epothilon, leur procede de production et leur utilisation pharmaceutique WO2000049019A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU38048/00A AU3804800A (en) 1999-02-18 2000-02-18 Novel epothilone derivatives, method for producing them and their pharmaceuticaluse

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DE19908760.1 1999-02-18
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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002067941A2 (fr) * 2001-02-27 2002-09-06 Novartis Ag Combinaison comprenant un inhibiteur de transduction de signaux et un derive d'epothilone
WO2003007924A2 (fr) * 2001-07-19 2003-01-30 Novartis Ag Combinaisons comprenant des epothilones et utilisations pharmaceutiques de celles-ci
WO2003078411A1 (fr) 2002-03-12 2003-09-25 Bristol-Myers Squibb Company Derives de c3-cyano epothilone
WO2006066949A1 (fr) 2004-12-23 2006-06-29 Bayer Schering Pharma Aktiengesellschaft Compositions comportant une epothilone et procedes de production associes
EP2065054A1 (fr) 2007-11-29 2009-06-03 Bayer Schering Pharma Aktiengesellschaft Combinaisons comprenant une prostaglandine et leurs utilisations
EP2070521A1 (fr) 2007-12-10 2009-06-17 Bayer Schering Pharma Aktiengesellschaft Nanoparticules à surface modifiée
DE102007059752A1 (de) 2007-12-10 2009-06-18 Bayer Schering Pharma Aktiengesellschaft Funktionalisierte, feste Polymernanopartikel enthaltend Epothilone
AU2008203233B2 (en) * 2001-07-19 2010-04-29 Novartis Ag Combinations comprising epothilones and pharmaceutical uses thereof
EP2210584A1 (fr) 2009-01-27 2010-07-28 Bayer Schering Pharma Aktiengesellschaft Composition polymère stable comprenant un copolymère séquencé d'épothilone et amphiphile
SG162616A1 (en) * 2002-06-10 2010-07-29 Novartis Ag Combinations comprising epothilones and pharmaceutical uses thereof
WO2013092998A1 (fr) 2011-12-23 2013-06-27 Innate Pharma Conjugaison enzymatique d'anticorps
WO2014140300A1 (fr) 2013-03-15 2014-09-18 Innate Pharma Conjugaison d'anticorps en phase solide médiée par la tgase
US9427478B2 (en) 2013-06-21 2016-08-30 Innate Pharma Enzymatic conjugation of polypeptides
US10036010B2 (en) 2012-11-09 2018-07-31 Innate Pharma Recognition tags for TGase-mediated conjugation
US10071169B2 (en) 2013-06-20 2018-09-11 Innate Pharma Enzymatic conjugation of polypeptides
US10132799B2 (en) 2012-07-13 2018-11-20 Innate Pharma Screening of conjugated antibodies
WO2019092148A1 (fr) 2017-11-10 2019-05-16 Innate Pharma Anticorps avec des résidus de glutamine fonctionnalisés

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4579351B2 (ja) 1996-12-03 2010-11-10 スローン−ケッタリング インスティトュート フォア キャンサー リサーチ エポチロンの合成とその中間体及びその類似物並びにその使用
SK11082003A3 (sk) * 2001-03-14 2004-08-03 Bristol-Myers Squibb Company Kombinácia analógov epotilónu a chemoterapeutických činidiel na liečenie proliferatívnych ochorení
US20030176368A1 (en) * 2001-09-06 2003-09-18 Danishefsky Samuel J. Synthesis of epothilones, intermediates thereto and analogues thereof
TWI287986B (en) * 2001-12-13 2007-10-11 Novartis Ag Use of Epothilones for the treatment of the carcinoid syndrome
DK1767535T3 (da) 2002-08-23 2010-04-12 Sloan Kettering Inst Cancer Syntese af epothiloner, mellemprodukter deraf, analoge og deres anvendelse
US7649006B2 (en) 2002-08-23 2010-01-19 Sloan-Kettering Institute For Cancer Research Synthesis of epothilones, intermediates thereto and analogues thereof
CN101360494A (zh) * 2005-11-22 2009-02-04 斯克里普斯研究学院 高效埃博霉素的化学合成

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997019086A1 (fr) * 1995-11-17 1997-05-29 GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) Derives d'epothilone, leur preparation et leur utilisation
WO1999007692A2 (fr) * 1997-08-09 1999-02-18 Schering Aktiengesellschaft Nouveaux derives d'epothilone, leur procede de fabrication et leur utilisation pharmaceutique
WO1999065913A2 (fr) * 1998-06-18 1999-12-23 GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) Constituants secondaires d'epothilone

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997019086A1 (fr) * 1995-11-17 1997-05-29 GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) Derives d'epothilone, leur preparation et leur utilisation
WO1999007692A2 (fr) * 1997-08-09 1999-02-18 Schering Aktiengesellschaft Nouveaux derives d'epothilone, leur procede de fabrication et leur utilisation pharmaceutique
WO1999065913A2 (fr) * 1998-06-18 1999-12-23 GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) Constituants secondaires d'epothilone

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
CHOU T C ET AL: "DESOXYEPOTHILONE B: AN EFFICACIOUS MICROTUBULE-TARGETED ANTITUMOR AGENT WITH A PROMISING IN VIVO PROFILE RELATIVE TO EPOTHILONE B" PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA,US,NATIONAL ACADEMY OF SCIENCE. WASHINGTON, Bd. 95, Nr. 16, 1998, Seiten 9642-9647, XP000910107 ISSN: 0027-8424 *
D SCHINZER ET AL: "ANGEWANDTE CHEMIE,DE,VCH VERLAGSGESELLSCHAFT, WEINHEIM" ANGEWANDTE CHEMIE,DE,VCH VERLAGSGESELLSCHAFT, WEINHEIM, Bd. 109, Nr. 5, 1997, Seiten 543-544, XP002095720 ISSN: 0044-8249 in der Anmeldung erw{hnt *
HANESSIAN, STEPHEN ET AL: "Total Synthesis and Absolute Configuration of (-)-Anthoplalone" J. ORG. CHEM. (1999), 64(13), 4893-4900 , XP002152894 *
K C NICOLAOU ET AL: "ANGEWANDTE CHEMIE,VCH VERLAGSGESELLSCHAFT, WEINHEIM,DE" ANGEWANDTE CHEMIE,VCH VERLAGSGESELLSCHAFT, WEINHEIM,DE, Bd. 109, Nr. 19, 1997, Seiten 2181-2187, XP002095723 ISSN: 0044-8249 in der Anmeldung erw{hnt *
K C NICOLAOU ET AL: "NATURE,MACMILLAN JOURNALS LTD. LONDON,GB" NATURE,MACMILLAN JOURNALS LTD. LONDON,GB, Bd. 387, Nr. 6630, 15. Mai 1997 (1997-05-15), Seiten 268-272, XP002095721 ISSN: 0028-0836 in der Anmeldung erw{hnt *
K C NICOLAOU ET AL: "Probing the ring size of epothilones: total synthesis of [14Ü-, [15Ü-, [17Ü-, and [18ÜEpothilones A" ANGEWANDTE CHEMIE. INTERNATIONAL EDITION,DE,VERLAG CHEMIE. WEINHEIM, Bd. 37, Nr. 1/02, 1998, Seiten 81-84, XP002131226 ISSN: 0570-0833 in der Anmeldung erwähnt *
ZHEN YANG ET AL: "ANGEWANDTE CHEMIE,DE,VCH VERLAGSGESELLSCHAFT, WEINHEIM" ANGEWANDTE CHEMIE,DE,VCH VERLAGSGESELLSCHAFT, WEINHEIM, Bd. 109, Nr. 1/02, 1997, Seiten 170-172, XP002095722 ISSN: 0044-8249 in der Anmeldung erw{hnt *

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WO2002067941A3 (fr) * 2001-02-27 2003-11-20 Novartis Ag Combinaison comprenant un inhibiteur de transduction de signaux et un derive d'epothilone
WO2002067941A2 (fr) * 2001-02-27 2002-09-06 Novartis Ag Combinaison comprenant un inhibiteur de transduction de signaux et un derive d'epothilone
AU2002308218B2 (en) * 2001-02-27 2005-11-10 Novartis Ag Combination comprising a signal transduction inhibitor and an epothilone derivative
US8008330B2 (en) 2001-07-19 2011-08-30 Novartis Ag Combinations comprising epothilones and pharmaceutical uses thereof
WO2003007924A3 (fr) * 2001-07-19 2003-09-25 Novartis Ag Combinaisons comprenant des epothilones et utilisations pharmaceutiques de celles-ci
AU2008203233B2 (en) * 2001-07-19 2010-04-29 Novartis Ag Combinations comprising epothilones and pharmaceutical uses thereof
AU2002328921B2 (en) * 2001-07-19 2006-11-02 Novartis Ag Combinations comprising epothilones and pharmaceutical uses thereof
AU2005246964B2 (en) * 2001-07-19 2008-04-24 Novartis Ag Combinations comprising epothilones and pharmaceutical uses thereof
EP2210643A3 (fr) * 2001-07-19 2010-11-24 Novartis AG Combinaisons comprenants des épothilones et leurs utilisations pharmaceutiques
WO2003007924A2 (fr) * 2001-07-19 2003-01-30 Novartis Ag Combinaisons comprenant des epothilones et utilisations pharmaceutiques de celles-ci
JP2010159271A (ja) * 2001-07-19 2010-07-22 Novartis Ag エポシロンを含有する組合せ剤およびその医薬上の使用
US7612052B2 (en) 2001-07-19 2009-11-03 Novartis Ag Combinations comprising epothilones and pharmaceutical uses thereof
WO2003078411A1 (fr) 2002-03-12 2003-09-25 Bristol-Myers Squibb Company Derives de c3-cyano epothilone
SG162616A1 (en) * 2002-06-10 2010-07-29 Novartis Ag Combinations comprising epothilones and pharmaceutical uses thereof
WO2006066949A1 (fr) 2004-12-23 2006-06-29 Bayer Schering Pharma Aktiengesellschaft Compositions comportant une epothilone et procedes de production associes
EP2371365A1 (fr) 2004-12-23 2011-10-05 Bayer Pharma Aktiengesellschaft Compositions comportant une épothilone et procédés de production associés
EP2065054A1 (fr) 2007-11-29 2009-06-03 Bayer Schering Pharma Aktiengesellschaft Combinaisons comprenant une prostaglandine et leurs utilisations
DE102007059752A1 (de) 2007-12-10 2009-06-18 Bayer Schering Pharma Aktiengesellschaft Funktionalisierte, feste Polymernanopartikel enthaltend Epothilone
EP2070521A1 (fr) 2007-12-10 2009-06-17 Bayer Schering Pharma Aktiengesellschaft Nanoparticules à surface modifiée
EP2210584A1 (fr) 2009-01-27 2010-07-28 Bayer Schering Pharma Aktiengesellschaft Composition polymère stable comprenant un copolymère séquencé d'épothilone et amphiphile
US9717803B2 (en) 2011-12-23 2017-08-01 Innate Pharma Enzymatic conjugation of polypeptides
US10675359B2 (en) 2011-12-23 2020-06-09 Innate Pharma Enzymatic conjugation of antibodies
WO2013092998A1 (fr) 2011-12-23 2013-06-27 Innate Pharma Conjugaison enzymatique d'anticorps
US9764038B2 (en) 2011-12-23 2017-09-19 Innate Pharma Enzymatic conjugation of antibodies
WO2013092983A2 (fr) 2011-12-23 2013-06-27 Innate Pharma Conjugaison enzymatique de polypeptides
US10132799B2 (en) 2012-07-13 2018-11-20 Innate Pharma Screening of conjugated antibodies
EP3564259A2 (fr) 2012-11-09 2019-11-06 Innate Pharma Étiquettes de reconnaissance pour la conjugaison à médiation par la tgase
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WO2014140300A1 (fr) 2013-03-15 2014-09-18 Innate Pharma Conjugaison d'anticorps en phase solide médiée par la tgase
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US10071169B2 (en) 2013-06-20 2018-09-11 Innate Pharma Enzymatic conjugation of polypeptides
US10434180B2 (en) 2013-06-21 2019-10-08 Innate Pharma Enzymatic conjugation of polypeptides
US9427478B2 (en) 2013-06-21 2016-08-30 Innate Pharma Enzymatic conjugation of polypeptides
WO2019092148A1 (fr) 2017-11-10 2019-05-16 Innate Pharma Anticorps avec des résidus de glutamine fonctionnalisés

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