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WO2000000485A1 - Derives d'epothilone, leur procede de production, produits intermediaires et leur utilisation pharmaceutique - Google Patents

Derives d'epothilone, leur procede de production, produits intermediaires et leur utilisation pharmaceutique Download PDF

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Publication number
WO2000000485A1
WO2000000485A1 PCT/EP1999/004915 EP9904915W WO0000485A1 WO 2000000485 A1 WO2000000485 A1 WO 2000000485A1 EP 9904915 W EP9904915 W EP 9904915W WO 0000485 A1 WO0000485 A1 WO 0000485A1
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Prior art keywords
methyl
dihydroxy
dione
ethenyl
general formula
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German (de)
English (en)
Inventor
Bernd Buchmann
Ulrich Klar
Werner Skuballa
Wolfgang Schwede
Michael Schirner
Andreas Menrad
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Bayer Pharma AG
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Schering AG
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Priority claimed from DE19830060A external-priority patent/DE19830060A1/de
Priority claimed from DE19923001A external-priority patent/DE19923001A1/de
Application filed by Schering AG filed Critical Schering AG
Priority to AU50369/99A priority Critical patent/AU5036999A/en
Publication of WO2000000485A1 publication Critical patent/WO2000000485A1/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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • 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
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring

Definitions

  • Epothilone derivatives processes for their preparation, intermediates and their pharmaceutical use
  • 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 done by improving the selectivity of the action and / or reducing undesirable toxic side effects and / or increasing the potency.
  • 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 al. described in WO 97/19086. These derivatives were made from the natural epothion A or B.
  • Another synthesis of epothilone and epothilone derivatives was by Nicolaou et al. in Angew. Chem. 1997, 109, No. 1/2, pp. 170-172.
  • R5 ', R8' have the meaning already given in the general formula I for R5 and R ⁇ and R20 is a hydrogen atom or a protective group PG ⁇
  • U is an oxygen atom, two alkoxy groups OR 9 , a C2-C- ⁇ o-alkylene- ⁇ , ⁇ -dioxy group, which can be straight-chain or branched, H / OR 10 or one
  • R9 represents a C 1 -C 20 -alkyl radical
  • R 1 1, R12 are the same or different and are hydrogen, a C 1 -C 20 -alkyl, aryl, C7-C20-aralkyl radical or R "1 1 and R 1 together with the methylene carbon atom together for a 5- to 7-membered carbocyclic ring W is an oxygen atom, two alkoxy groups OR21, a C2-C ⁇ rj-alkylene- ⁇ , ⁇ -dioxy group, which can be straight-chain or branched or H / OR22, where
  • R21 is a C 1 -C 20 -alkyl radical
  • R22 for hydrogen or a protective group PG 7 mean.
  • 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
  • Rl a R 1 b are the same or different and are hydrogen, C ⁇ -C-
  • o _ alkyl, aryl, C7-C20-aralkyl, or together a (CH2) m group with m 2, 3, 4 or 5,
  • R2a, R2b are the same or different and are hydrogen, C-
  • -C ⁇ o-alkyl, aryl, C7-C20 aralkyl or together a - (CH2) n group with n 2, 3, 4 or 5,
  • R 3 is hydrogen, C-
  • R 5 is C-1 -C-1 o-alkyl, aryl, C7-C20 ralkyl,
  • R 6 , R 7 each represent a hydrogen atom, together an additional bond or an oxygen atom, R25 hydrogen, C-
  • R 9 for a C 1 -C 20 -alkyl radical, RIO for hydrogen or a protective group PG 1 ,
  • R 1 1 , R 1 2 are the same or different and are hydrogen, a C 1 -C 20 -alkyl, aryl, C7-C20-aralkyl radical or R 1 1 and R 1 2 together with the methylene carbon atom together for a 5- to 7th -linked carbocyclic ring, Y is an oxygen atom or two hydrogen atoms,
  • Z is an oxygen atom or H / OR 1 3 , where R ⁇ 3 is hydrogen or a protective group PG2, including all stereoisomers of these compounds and also mixtures thereof.
  • the presentation of the new epothilone derivatives is based on the linkage of three partial fragments A, B and C and is carried out in the same way as for epothilone A and epothilone B derivatives (ie there can only be one hydrogen atom in the place of R ⁇ ) in WO 99/07692 is described.
  • the interfaces are as indicated in the general formula I '.
  • A represents a C1-C6 fragment (epothiion counting) of the general formula
  • R 1 a ', R', R2a ' and R 2b " d j e already have the meanings given for Ria, Rl b t R2a and j R2b and
  • R1 4 CH 2 OR 1 a , CH 2 -Hal, CHO, CO 2 R 14 , COHal,
  • R15 hydrogen, OR 15a , shark, OSO 2 R 15b ,
  • Rl4a t Rl 5a hydrogen, S ⁇ 2-alkyl, SO2-A17I, S ⁇ 2-aralkyl or together a - (CH2) o group or together a CR 16a R 1 6 group,
  • Rl4b t R 15b hydrogen, -CC 20 alkyl, aryl, C 7 -C 2 o-aralkyl,
  • R 16a t R 16b are the same or different and are hydrogen, C ⁇
  • R 4a ', R 4b ' and R 25 have the meanings already mentioned for R 3 , R a, R4b and R 25, and
  • R 17 is a hydroxy group, halogen, a protected hydroxy group OPG 3
  • Phosphine oxide residue P (0) P 2 (Ph phenyi), V one oxygen atom, two alkoxy groups OR 1 8 , one C2-C-
  • R 19 represents a hydrogen or a protective group PG 4 .
  • R 5 ' , R 8 ' have the meaning already given in general formula I for R 5 and R 8 and
  • R20 is a hydrogen atom or a protective group PG ⁇
  • U is an oxygen atom, two alkoxy groups OR 9 , a C2-C- ⁇ o-alkyien- ⁇ , ⁇ -dioxy group, which can be straight-chain or branched, H / OR 10 or a group CR 1 1 R 12 , where
  • R 9 represents a C 1 -C 20 -alkyl radical
  • R 1 1 , R 1 2 are the same or different and are hydrogen, a C 1 -C 20 -alkyl, aryl, C7-C20-aralkyl radical or R 1 1 and R 12 together with the methylene carbon atom together for a 5th - to 7-membered carbocyclic ring
  • W is an oxygen atom, two alkoxy groups OR 21 , a C2-C- ⁇ o-alkylene- ⁇ , ⁇ -dioxy group, which can be straight-chain or branched or H / OR 22 , where
  • R 21 represents a C -C20 alkyl radical
  • R 22 represents hydrogen or a protective group PG 7 .
  • R 4_ R 5_ R 16a t R 16b and R 25 are straight . or branched-chain alkyl groups with 1-10 cone tensor atoms to oetractene, such as, for example, methyl. Ethyl, propyl, isopropyl. Butyl, isobutyl, tert-butyl. Pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl.
  • alkyl groups R 8 , R 9 , R 1 0 , R 1 1 , R * 2 ; R 1 3, Rt b, R 5b and R 1 8 g are to be regarded he ad or verzweigtkertige alkyl groups having 1 -20 Kohlenstoffatome ⁇ ; such as the residues mentioned by name in the preceding paragraph and their corresponding higher homologues.
  • R 16b and R 18 may be perfluorinated or substituted by 1-5
  • Halogen atoms hydroxyl groups, C-
  • R 1 8a and R 1 8 come substituted and unsubstituted carbocyclic or heterocyclic radicals having one or more heteroatoms such as, for example, phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyi, pyrazinyi, quinolyi, thiazolyl, the single or multiple can be substituted by halogen, OH, O-alkyl, CO2H, CO 2 -alkyl, -NH 2 , -NO 2 , -N3, -CN, C -C 2 o-alkyl, C ⁇
  • halogen OH, O-alkyl, CO2H, CO 2 -alkyl, -NH 2 , -NO 2 , -N3, -CN, C
  • R 16a and 16b can contain up to 14 carbon atoms, preferably 6 to 10, in the ring and 1 to 8, preferably 1 to 4, atoms in the alkyl chain.
  • suitable aralkyl radicals are benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, thienylethyl, pyridylpropyl.
  • the rings can be mono- or polysubstituted by halogen, OH, O-alkyl, CO2H, CO 2 -alkyl, -NO2, -N3, -CN, C-
  • the alkoxy groups contained in X in the general formula I should each contain 1 to 20 carbon atoms, with methoxy, ethoxy-propoxy-isopropoxy and t-butyloxy groups being preferred.
  • Representing the protective groups PG are alkyl- and / or aryl-substituted silyl, C-
  • alkyl, silyl and acyl radicals for the protective groups PG are the radicals known to the person skilled in the art. Easily removable alkyl or silyl radicals, such as, for example, are preferred from the corresponding alkyl and silyl ethers
  • Alkylsulfo ⁇ yl- and arylsulfonyl residues are formyl, acetyl, propionyl, Isopropionyl, pivalyi. Butyryl or Benzoyi, which can be substituted with amino and / or hydroxy groups, in question.
  • the acyro groups PG "1 and PG 2 in R “ 1 0 and R 1 3 can contain 1 to 20 carbon atoms, formyl, acetyl, propionyl, isopropionyl and pivalyl groups being preferred.
  • the index m in the alkylene group formed from R 1 a and R 1 b is preferably 2, 3 or 4.
  • o-Alkylene- ⁇ , ⁇ -dioxy group is preferably an ethylene ketal or neopentyl keta group.
  • the radical R 25 is preferably a hydrogen atom, a methyl, ethyl, propyl, hydroxymethyl, fluoromethyl or trifluoromethyl group.
  • R 3 , R 4a , R 4b , DE, R 5 , R 6 , R 25 and R 7 can all have the meanings given in general formula I, and the rest of the molecule is identical to the naturally occurring epothilone A or B. or
  • R 5 , R 6 , R 25 , R 7 , R 8 and X can all have the meanings given in the general formula I, and the rest of the molecule is identical to the naturally occurring epothiion A or B or
  • R 3 , R 4a , R 4b , DE, R 5 , R 6 , R 25 , R 7 , R 8 and X can all have the meanings given in general formula I, and the rest of the molecule is identical to that which occurs naturally Epothilon A or B.
  • a further variant according to the invention provides those compounds in which R ⁇ is stent for a methyl, ethyl or propylene group. wooei then preferably R ⁇ un ⁇ R 7 together mean an additional bond or an epoxy group.
  • the partial fragments (synthesis building blocks) of the general formula A can easily be obtained from a) a pantolactone of the general formula Ila
  • Rla ' t Rlb' each represent a methyl group or b) a malonic acid dialkyl ester of the general formula XXVII
  • Alkyl independently of one another a C-
  • Alkyicycloalkylrest mean.
  • pantolactone (A-II) is protected by the methods known to those skilled in the art.
  • protective group PG ⁇ come the protective groups known to the person skilled in the art, such as, for example, methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert.-butyldimethylsilyl, tert.-butyldiphenylsilylsilyl, tribenzylsilyl, tribenzylsilyl, tribenzylsilyl -, Benzyi, para-nitrobenzyl, para-methoxybenzyl, formyl, acetyl, propionyl, isopropionyl, pivalyl, butyryl or benzoyl in question.
  • the protected lactone A-Ill is reduced to lactol A-IV.
  • Reactivity modified aluminum hydrides such as e.g. Diisobutyl aluminum hydride.
  • the reaction takes place in an inert solvent such as e.g. Toluene, preferably at low temperatures.
  • Lactol A-IV is opened with the addition of one carbon atom to the hydroxyolefin A-V.
  • Methyl triphenylphosphonium bromide with strong bases such as e.g. n-butyl lithium, potassium tert-butanoate, sodium ethanolate, sodium hexamethyldisiiazane; n-butyllithium is preferred as the base.
  • the free hydroxyl group in AV is protected by methods known to those skilled in the art.
  • Protective groups which can be cleaved under the action of fluoride such as e.g. the trimethylsilyl, tert.-butyldimethylsilyl, tert.-
  • Anti-Markovnikov water is added to the double bond in A-VI.
  • the processes known to the person skilled in the art are suitable for this purpose, for example the reaction with boranes, their subsequent oxidation to the corresponding boric acid esters and their saponification.
  • Preferred boranes are, for example, the borane-tetrahydrofuran complex, the borane-dimethyl sulfide complex, 9-borabicyclo [3.3.1] nonane in an inert solvent such as, for example, tetrahydrofuran or diethyl ether.
  • an oxidizing agent preferably hydrogen peroxide, preferably alkali metal hydroxides such as sodium hydroxide for the saponification of the boresters
  • Step f (A-VI »A-VII):
  • the protective group PG 8 introduced under step a) is now cleaved according to the processes known to the person skilled in the art. If it is an acidic cleavable protective group, then dilute mineral acids in aqueous alcoholic solutions are suitable, the use of catalytic amounts of acids such as para-toluenesulfonic acid, para-toluenesulfonic acid pyridinium salt, camphorsulfonic acid in alcoholic solutions, preferably in ethanol or Isopropanol.
  • Suitable acids are the acids already mentioned under step f), preference is given to the use of para-toluenesulfonic acid, optionally with the addition of copper (II) or cobalt (II) salts such as copper (II) sulfate.
  • the protective group PG introduced under step d) is then split using the methods known to the person skilled in the art. If it is a silyl ether, the reaction with fluorides such as tetrabutylammonium fluoride, the hydrogen fluoride-pyridine complex, potassium fluoride or the use of dilute mineral acids, the use of catalytic amounts of acids such as para-toluenesulfonic acid, para-toloisoisifonic acid is suitable for the cleavage -pyndinium salt, Campner sulfonic acid in alcoholic solutions, preferably in ethanol or isopropanol.
  • fluorides such as tetrabutylammonium fluoride, the hydrogen fluoride-pyridine complex, potassium fluoride or the use of dilute mineral acids
  • the use of catalytic amounts of acids such as para-toluenesulfonic acid, para-toloisoisifonic acid is suitable for the cleavage -pyndinium salt, Camp
  • Step k (A-X A-Xl):
  • the oxidation of the primary alcohol in A-X to the aldehyde takes place according to the methods known to the person skilled in the art. Examples include oxidation with pyridinium chlorochromate, pyridinium dichromate, chromium trioxide-pyridine complex, oxidation according to Swern or related methods, e.g. using oxalyl chloride in dimethyl sulfoxide, using Dess-Martin periodinane, using nitrogen oxides such as e.g. N-methyl-morpholino-N-oxide in the presence of suitable catalysts such as e.g. Tetrapropylammonium perruthenate in inert solvents. Oxidation according to Swern and with N-methyl-morpholino-N-oxide using tetrapropylammonium perruthenate is preferred.
  • organometallic compounds of the general formula M-CHR a 'R 2 ' in which M is an alkali metal, preferably lithium or a divalent metal MX, in which X represents a halogen and the radicals R 2a 'and R 2b ' each have the meanings given above.
  • M is an alkali metal, preferably lithium or a divalent metal
  • X represents a halogen
  • the radicals R 2a 'and R 2b ' each have the meanings given above.
  • Magnesium and zinc are preferred as divalent metal, and chlorine, bromine and iodine are preferred as halogen X.
  • R 2a 'in A-Xlll is hydrogen
  • R 2a ' which has the meanings mentioned above, except hydrogen
  • R 2a ' is hydrogen
  • R 2a ' is hydrogen
  • R 2a ' is hydrogen
  • X represents a halogen
  • Halogen X is preferably chlorine, bromine and iodine.
  • the previously described route can also be used to synthesize C1-C6 epothilone building blocks which contain a carboxylic acid or its ester at C-1
  • the synthesis of the building block A-XXII is described in the following scheme 2 using the example of the intermediate AV derived from D - (-) - pantolactone.
  • the corresponding compounds ent-AV to ent-A-XXVII which are enantiomeric to AV to A-XXVII are obtained from L - (+) - pantolactone and the corresponding racemic compounds rac-AV to rac-A-XXVII from racemic DL-pantolactone:
  • Step k conditions mentioned.
  • the oxidation method according to Swern is preferred.
  • organometallic compounds of the general formula M-CHR 2a 'R 2b ' in which M is an alkali metal, preferably lithium or a divalent metal MX, in which X represents a halogen and the radicals R 2a 'and R 2b ' each have the meanings given above.
  • M is an alkali metal, preferably lithium or a divalent metal
  • X represents a halogen
  • the radicals R 2a 'and R 2b ' each have the meanings given above.
  • Magnesium and zinc are preferred as divalent metal, and chlorine, bromine and iodine are preferred as halogen X.
  • Anti-Markovnikov water is added to the double bond in A-XVI.
  • the methods described under e) are suitable for this.
  • the free hydroxyl group in A-XVI I is protected by the methods known to those skilled in the art.
  • Reaction conditions can be split, e.g. Benzyi, para-nitrobenzyl,
  • Acetyl, propionyl, butyryl, benzoyl radical is particularly preferred.
  • the protection group PG 10 in XIX is now split selectively. If it is a hydrogenolytically cleavable protective group, hydrogenation is preferably carried out in the presence of palladium or platinum catalysts in inert solvents such as, for example, ethyl acetate or ethanol. If it is a basic cleavable protective group, use is preferably made of saponification with carbonates in alcoholic solution, such as, for example, potassium carbonate in methanol, and saponification with aqueous solutions of alkali metal hydroxides, such as, for example, lithium hydroxide or sodium hydroxide Use of organic, water-miscible solvents such as methanol. Ethanol, tetranydrofuran or dioxane.
  • the oxidation of the aldehyde in A-XXI to the carboxylic acid A-XXII takes place according to the methods known to the person skilled in the art.
  • Examples include oxidation according to Jones, oxidation with potassium permanganate, for example in an aqueous system composed of tert-butanol and sodium dihydrogen phosphate, oxidation with sodium chlorite in aqueous tert-butanol, if appropriate in the presence of a chlorine scavenger such as 2-methyl-2-butene.
  • the oxidation of the aldehyde in A-XXI to the ester A-XXII, in which R 14 b has the meanings given above and is not hydrogen, can be carried out, for example, with pyridinium dichromate and the desired alcohol HO-R 14b in an inert solvent such as dimethylformamide.
  • the protection group PG ⁇ introduced under step d) is split as described under step i Step aa i .
  • A-XXV > A-XXVI):
  • R 1 a ' and d Rlb' can all have the meanings given in the general formula A, can also be prepared efficiently and with high optical purity from cheap or easily accessible malonic acid dialkyl esters.
  • A-XXVIII Correspondingly substituted malonic acid ester derivatives A-XXVIII, which are either commercially available or can be prepared from malonic acids or their alkyl esters by methods known to the person skilled in the art, are reduced to diols A-XXIX.
  • the reducing agents known to the person skilled in the art e.g. Diisobutyl aluminum hydride, complex metal hydrides such as e.g. Lithium aluminum hydride.
  • a free hydroxyl group in A-XXIX is selectively protected by methods known to those skilled in the art.
  • the aldehydes A-XXXI are reacted with an ester of acetic acid chG 1 OC (0) CH3, in which chG 1 is a chiral auxiliary group, in the sense of an aldol reaction.
  • the compounds chG 1 OC (0) CH3 are used in optically pure form in the aldol reaction.
  • the type of chiraic auxiliary group determines whether the aldol reaction proceeds with high diastereoselectivity or results in a diastereomer mixture that can be separated by physical methods. An overview of comparable diastereoselective aldol reactions can be found in Angew. Chem.
  • chiraie auxiliary groups chG ⁇ -OH for example, optically pure 2-phenyi-cyclohexanol, pulegol, 2-hydroxy-1, 2,2-triphenylethanol, 8-phenylmenthol are suitable.
  • the diastereomerically pure compounds A-XXXII can then be converted into enantiomerically pure compounds of the type A-XXXIII or ent-A-XXXIII by saponification of the ester unit with simultaneous release of the reusable chiral auxiliary component chG 1 -OH by processes known to the person skilled in the art.
  • Suitable for saponification are carbonates in alcoholic solution such as, for example, potassium carbonate in methanol, aqueous solutions of alkali hydroxides such as, for example, lithium hydroxide or sodium hydroxide using organic, water-miscible solvents such as, for example, methanol, ethanol, tetrahydrofuran or dioxane.
  • the chiraie auxiliary group can also be removed reductively.
  • the enantiomerically pure compounds of the type A-VIII or ent-A-VIII are obtained.
  • the reduction can be carried out according to the methods known to the person skilled in the art.
  • reducing agents are e.g. Diisobutyl aluminum hydride and complex metal hydrides such as e.g. Lithiumiumiumiumhydrid in question.
  • the compounds A-VIII or ent-A-VIII can, as described above, be converted into compounds of the type A-Xlll or ent-A-XIII.
  • compounds of type A-XXXIII or ent-A-XXXIII can be converted into compounds of type A-XXII or ent-A-XXH according to the methods described above.
  • the sequence can also be carried out without using a chiral auxiliary group chG ' '.
  • racemic mixtures of compounds of the type rac-A-III or rac-A-XXXHI are then receive the corresponding racemic precursors.
  • These mixtures can in turn be separated according to the methods known to those skilled in the art for resolving racemates, for example chromatography on chiral columns.
  • the synthesis can also be continued with the racemic mixtures.
  • a hydroxyl group in B-II is protected by the methods known to the person skilled in the art.
  • Protective groups containing silicon which can be cleaved under acidic reaction conditions or using fluoride, such as, for example, the trimethylsilyl, T ⁇ ethylsilyl- tert -Butyldimethylsilyl- tert -Butyldiphenvisilyl- T ⁇ benzylsilyl-
  • the tert-butyldimethylsilyi radical is particularly preferred
  • the free hydroxyl group in B-III is converted into a leaving group LG by the methods known to the person skilled in the art.
  • Halogens such as e.g. Bromine or iodine or alkyl or aryl sulfonates which are prepared from the corresponding sulfonic acid halides or sulfonic acid anhydrides by the methods known to the person skilled in the art.
  • Trifluoromethane suifonate is preferred as the leaving group LG.
  • the compound B-IV is alkylated with the enolate of a carbonyl compound of the general formula BV, in which chG 2 can be a simple alkoxy group or a chiral auxiliary group, by the methods known to the person skilled in the art.
  • the enolate is produced by the action of strong bases such as lithium diisopropylamide, lithium hexamethyidisilazane at low temperatures.
  • the chiraie auxiliary group chG 2 -H (B-VI) are chiraie, optically pure and inexpensive alcohols such as pulegol, 2-phenylcyclohexanol, 2-hydroxy-1, 2,2-t ⁇ phenylethanol, 8-phenylmenthol or optically pure and inexpensive, reactive NH-containing compounds such as nurse, amino acids, lactams or oxazolidinones.
  • Oxazolidinones are preferred, particularly preferably the compounds of the formulas B-Vla to B-Vld.
  • the choice of the respective antipode determines the absolute stereochemistry of the ⁇ -carbonyl carbonate of the compound of the general formula B-VIII.
  • the compounds of the general formulas B-VIII to B-XVII or their respective enantiomers ent-B-VII to ent-B-XVII can be obtained in an e ⁇ antiomerically pure manner. If an achira alcohol such as ethanol is used as chG 2 -H (B-VI), the racemic compounds rac-B-VII to rac-B-XVII are obtained.
  • step c the group chG 2 represents one of the chiral auxiliary groups mentioned under step c, this is recovered by transesterification of B-VIII into an alkyl ester of the general formula B-VIII.
  • the ester in 3-VIII is ⁇ converted to the Alkonol 3-iX.
  • Suitable reducing agents are the reducing agents known to the person skilled in the art, such as aluminum hydrides such as lithium aluminum hydride or diisobutyl aluminum hydride.
  • the reaction takes place in an inert solvent such as e.g. Diethyl ether, tetrahydrofuran, toluene.
  • the carbonyi group in B-VIII can be reduced directly to the alcohols of the general formula B-IX under the conditions mentioned under step e).
  • the chiraie auxiliary component chG 2 -H can also be recovered here.
  • the primary hydroxyl group in B-IX is first oxidized to the corresponding aldehyde by methods known to those skilled in the art.
  • Examples include oxidation with py ⁇ dinium chlorochromate, py ⁇ dinium dichromate, chromium oxide-py ⁇ din complex, oxidation by Swern or related methods, for example using oxalyl chloride in dimethyl sulfoxide, using Dess-Martin penodinane, using nitrogen oxides such as N-methyl morpholino-N-oxide in the presence of suitable catalysts such as tetrapropylammonium perruthenate in inert solvents.
  • Oxidation according to Swern and with N-methyl-morpholino-N-oxide using tetrapropylammonium perruthenate is preferred.
  • the aldehydes thus obtained can then be converted into corresponding alcohols with organometallic compounds of the general formula MR ⁇ , where M is an alkali metal, preferably lithium or a divalent metal MX, where X represents a halogen and the radical R3 has the meanings given above.
  • M is an alkali metal, preferably lithium or a divalent metal MX, where X represents a halogen and the radical R3 has the meanings given above.
  • Magnesium and zinc are preferred as the divalent metal
  • halogen X is preferably chlorine, bromine and iodine.
  • the protective group PG ' ' 2 which has been darkened in step a), is now split according to the process known to a person. If it is a silyl ether, the reaction with fluons such as tetrabutylammonium fluoride, the hydrogen fluoride-pyrin complex, potassium fluoride is suitable for the split or the use of dilute mineral acids, the use of catalytic amounts of acids such as, for example, para-toluenesulfonic acid, para-toluoisulfonic acid py ⁇ dinium salt, camphorsulfonic acid in alcoholic solutions, preferably in ethanol or isopropanol.
  • fluons such as tetrabutylammonium fluoride, the hydrogen fluoride-pyrin complex, potassium fluoride is suitable for the split or the use of dilute mineral acids, the use of catalytic amounts of acids such as, for example, para-toluenesulfonic acid, para-toluoisulfonic acid
  • R 25 is not a hydrogen atom
  • the primary hydroxyl group in B-Xl is first oxidized to the corresponding aldehyde by methods known to those skilled in the art.
  • Examples include oxidation with pyndinium chlorochromate, pyndinium dichromate, chromium oxide-pyridine complex, oxidation according to Swern or related methods, for example using oxalyl chloride in dimethyl sulfoxide, the use of Dess-Martin-Pe ⁇ odinans, the use of nitrogen oxides such as N-methyl morpholino-N-oxide in the presence of suitable catalysts such as tetrapropylammonium perruthenate in inert solvents. Oxidation according to Swern and with N-methyl-morpholino-N-oxide using tetrapropylammonium perruthenate is preferred.
  • the aldehydes thus obtained can then be converted into corresponding alcohols with organometallic compounds of the general formula MR 2 ⁇ , where M is an alkali metal, preferably lithium or a divalent metal MX, where X represents a halogen and the radical R 2 ⁇ has the meanings given above.
  • M is an alkali metal, preferably lithium or a divalent metal MX, where X represents a halogen and the radical R 2 ⁇ has the meanings given above.
  • M is an alkali metal, preferably lithium or a divalent metal MX, where X represents a halogen and the radical R 2 ⁇ has the meanings given above.
  • M is an alkali metal, preferably lithium or a divalent metal MX
  • X represents a halogen
  • R 2 ⁇ has the meanings given above.
  • Magnesium and zinc are preferred as divalent metal, and chlorine, bromine and iodine are preferred as halogen X.
  • the free primary hydroxyl group is converted into a halide by the processes known to the person skilled in the art.
  • Preferred halides are chlorine, but especially bromine and iodine.
  • the substitution of the hydroxyl group for a bromine can e.g. by means of triphenylphosphine / tetrabromomethane but also by any other process known to the person skilled in the art.
  • the establishment of an iodine atom can be derived from the bromide by substitution e.g. according to Finkelstein with sodium iodide in acetone. Direct conversion of the hydroxyl group into the iodide is also possible, e.g. using elemental iodine, imidazole and T ⁇ phenylphosphin in dichloromethane.
  • phosphonium salts e.g. the reaction of the corresponding halides with triphenylphosphine in solvents such as toluene or benzene, optionally in the presence of a base such as triethylamine or diisopropylethylamine.
  • the representation of the phosphonates can e.g. by reaction of the halides B-Xl with a metalated dialkyl phosphite.
  • the metalation is usually done with strong bases such as Butyllithium.
  • the representation of the phosphine oxides can e.g. by reaction of the halides B-Xl with metallized diphenylphosphine and subsequent oxidation. Strong bases such as butyllithium are also suitable for the metalation.
  • the subsequent oxidation to phosphine oxide can then e.g. with dilute aqueous hydrogen peroxide solution.
  • the compounds of the general formula B-XIII can be prepared via the route described in Scheme 5.
  • ester enolate is prepared by the action of strong bases such as lithium diisopropylamide, lithium hexamethyldisilazane at low temperatures and with 3-halogen -1-propyne, preferably 3-bromo-1-propyne, to give compounds of the general formula B-XV.
  • strong bases such as lithium diisopropylamide, lithium hexamethyldisilazane at low temperatures and with 3-halogen -1-propyne, preferably 3-bromo-1-propyne
  • the ester 3-XV is reduced to the alcohol B-XVI by the methods described in step e), preferably using diisobutylaluminum hydride.
  • R 3 is not a hydrogen atom
  • the primary hydroxyl group in B-XVI is first oxidized to the corresponding aldehyde by methods known to those skilled in the art. Examples include oxidation with pyridinium chlorochromate, pyridinium dichromate, chromium trioxide-pyridine complex, oxidation according to Swern or related methods, for example using oxalyl chloride in dimethyl sulfoxide
  • N-methyl-morpholino-N-oxide in the presence of suitable catalysts such as e.g.
  • Tetrapropylammonium perruthenate in inert solvents Oxidation according to Swern and with N-methyl-morpholino-N-oxide using is preferred
  • Alkali metal preferably lithium or a divalent metal MX, in which X represents a halogen and the radical R 3 has the meanings given above.
  • X represents a halogen and the radical R 3 has the meanings given above.
  • Magnesium and zinc are preferred as the divalent metal, and X is preferred as the halogen
  • Chlorine, bromine and iodine Chlorine, bromine and iodine.
  • Case R 3 H the free hydroxyl group in B-XVII is protected by the methods known to the person skilled in the art.
  • the protective group PG 14 includes those known to the person skilled in the art
  • Protective groups containing silicon which can be cleaved under acidic reaction conditions or using fluoride, such as e.g. the trimethylsilyl, triethylsilyl, tert.-butyldimethylsilyl, tert.-butyldiphenylsilyl, tribenzyisilyl,
  • the tert-butyldimethylsilyl radical is particularly preferred.
  • Step n (B-XVII > B-Xl):
  • the acetylene B-XVII can be deprotonated by the processes known to the person skilled in the art and the acetylide obtained can be reacted with formaldehyde to give an alcohol of the general formula B-XI.
  • Alkyl alkali compounds such as butyl lithium or other strong bases such as alkali hexamethyl disilazanes or lithium diisopropyl amide are suitable for deprotonation.
  • ⁇ -Butyllithium is preferred.
  • the racemic compounds rac-B-XI are obtained first.
  • the continuous steps rac-B-XV or rac-B-XVI according to Scheme 6 offer the possibility of chemical resolution and thus also access to the enantiomerically rare compounds B-XVI or ent-B-XVI, provided that R ⁇ a ' is not identical to R 4 '.
  • the racemic compound rac-B-XV can be transesterified with a chiral, optically obtainable alcohol chG 3 -OH by the methods known to the person skilled in the art, for example the process mentioned under step d), to give a mixture of the diastereomeric esters B-XVa and with separate simple chromatographic methods.
  • Possible chiral alcohols are, for example, pulegol, 2-phenylcyclohexanol, 2-hydroxy-1,2,2-triphenylethanol, 8-phenylmenthol.
  • the diastereomerically pure esters B-XVa can each be reduced to the alcohols B-XVI or ent-B-XVI by the process described in step e, the auxiliary component chG 3 -OH described in step o being able to be recovered.
  • the racemic compound rac-B-XVI can be converted to a mixture of the diastereomeric esters B-XVIa with a chiral, optically purely obtainable acid chG 4 -C02H, its ester, anhydride or acid halide by the methods known to the person skilled in the art and with simple chromatographic Separate methods.
  • Suitable chiraic acids are, for example, malic acid, tartaric acid or their derivatives.
  • the diastereomerically pure esters B-XVIa can each be reduced to the alcohols B-XVI or ent-B-XVI by the process described under step e, or saponified by the methods known to the person skilled in the art, in which case the auxiliary comp described in step u ⁇ nente chG ⁇ -C02H can be recovered.
  • Partial fragments of formula C can be produced from inexpensive, inexpensive malic acid in an efficient manner with high optical purity (> 99.5% ee).
  • protecting groups which can be cleaved under the action of fluoride but are stable under weakly acidic reaction conditions, such as, for example, the tert-butyldiphenylsilyl, tert-butyldimethylsilyl or triisopropylsilyl radical.
  • the tert-butyldiphenylsilyl and the tert-butyldimethylsilyl radical are particularly preferred.
  • the lactone C-III is reduced to lactol C-IV by the methods known to the person skilled in the art.
  • Reactivity modified aluminum hydrides such as e.g. Diisobutyl aluminum hydride.
  • the reaction is carried out in an inert solvent such as e.g. Toluene, preferably at low temperatures (-20 to -100 ° C).
  • the primary hydroxyl group in compound C-V is selectively protected against the secondary hydroxyl group by the methods known to the person skilled in the art.
  • Preferred protective groups are those which can be cleaved under weakly acidic reaction conditions, such as e.g. the trimethylsilyl-, triethylsilyl, -tert.-
  • the tert-butyldimethylsilyl radical is particularly preferred.
  • the oxidation of the secondary alcohol in C-Vl to the ketone C-Vll takes place according to the methods known to the person skilled in the art. Examples include oxidation with pyridinium chlorochromate, pyridinium dichromate, chromium trioxide-pyridine complex, oxidation by Swern or related methods, for example using oxalyl chloride in dimethyl sulfoxide, the use of Dess-Martin periodinane, the use of nitrogen oxides such as N-methyl morpholino-N-oxide in the presence of suitable catalysts such as tetrapropylammonium perruthenate in inert solvents. Swern oxidation is preferred.
  • the Wittig and Wittig / Homer reaction is preferred using phosphonium halides of the type CR 1 1 'R 1 2 ' P (Ph) 3 + Ha
  • the ketone is by the methods known to the person skilled in the art, for example using an alcohol H ⁇ R 9 or a C2-C ⁇ o-alkylene- ⁇ , ⁇ - diols ketalinstrument under acid catalysis.
  • the protective group PG 18 introduced under e is now selectively cleaved in the presence of PG 1 ⁇ using the processes known to those skilled in the art. If the protective group can be split off with acid, the cleavage is preferably carried out under weakly acidic conditions, such as, for example, by reaction with dilute organic acids in inert solvents. Acetic acid is preferred.
  • the oxidation of the primary alcohol in C-IX to the aldehyde of the general formula C-X takes place according to the methods known to the person skilled in the art.
  • Examples include oxidation with pyridinium chlorochromate, pyridinium dichromate, chromium trioxide-pyridine complex, oxidation according to Swern or related methods, e.g. using oxalyl chloride in dimethyl sulfoxide, using Dess-Martin periodinane, using nitrogen oxides such as e.g. N-methyl-morpholino-N-oxide in the presence of suitable catalysts such as e.g. Tetrapropylammonium perruthenate in inert solvents. Oxidation according to Swern and with N-methyl-morpholino-N-oxide using tetrapropylammonium perruthenate is preferred.
  • Step k (CX C-XI):
  • the conversion of the aldehydes CX to alcohols of the general formula C-XI takes place according to the methods known to the person skilled in the art with organometallic compounds of the general formula MR ⁇ ', where M is an alkali metal, preferably lithium or a divalent metal MX, where X represents a halogen and the rest R ⁇ 'the above has the meaning mentioned.
  • M is an alkali metal, preferably lithium or a divalent metal MX, where X represents a halogen and the rest R ⁇ 'the above has the meaning mentioned.
  • Magnesium and zinc are preferred as divalent metal, and chlorine, bromine and iodine are preferred as halogen X.
  • the alcohol C-XI is oxidized to the ketone of the general formula C-XII by the processes mentioned under k) or by Jones oxidation. Oxidation according to Jones is preferred.
  • the compound B in which R 1 7 has the meaning of a Wittigsaize and any additional carbonyl groups that may be present are protected, is deprotonated by a suitable base such as, for example, n-butyllithium, lithium diisopropylamide, potassium tert-butoxide, sodium or lithium hexamethyldisilazide and with a compound C, in which W has the meaning of an oxygen atom.
  • a suitable base such as, for example, n-butyllithium, lithium diisopropylamide, potassium tert-butoxide, sodium or lithium hexamethyldisilazide
  • W has the meaning of an oxygen atom.
  • the compound BC in which V has the meaning of an oxygen atom and any additional carbonyl groups which may be present are protected, is alkylated with the enolate of a carbonyl compound of the general formula A, in which Z has the meaning of an oxygen atom.
  • the enolate is formed by the action of strong bases such as e.g. Lithium diisopropylamide, lithium hexamethyldisilazane produced at low temperatures.
  • the compounds ABC in which R 14 is a carboxylic acid CO2H and R 20 is a hydrogen atom, are set according to the methods known to the person skilled in the art for the formation of large macrolides to give compounds of the formula I in which Y is of an oxygen atom, in order.
  • the method described in "Reagents for Organic Synthesis, Vol. 16, p 353" is preferred using 2,4,6-trichiorbenzoic acid chloride and suitable bases such as, for example, triethylamine, 4-dimethylaminopyridine and sodium hydride.
  • the compounds ABC in which R 14 represents a group CH2OH and R 20 represents a hydrogen atom, can preferably be converted into compounds of the formula I, in which Y has the meaning of two hydrogen atoms, using triphenylphosphine and azodiesters such as, for example, diethyl azodicarboxylate.
  • the compounds ABC in which R 14 represents a group CH2 ⁇ S ⁇ 2alkyl or CH2 ⁇ S ⁇ 2Aryl or CH2 ⁇ S ⁇ 2Aralkyl and R 20 represents a hydrogen atom, can be deprotonated with suitable bases such as sodium hydride, n-butyllithium, 4-dimethylaminopyridine, Hünig base, alkylhexamethyldisilazanes to give the compounds of the compounds I, in which Y has the meaning of two hydrogen atoms, cyclize.
  • suitable bases such as sodium hydride, n-butyllithium, 4-dimethylaminopyridine, Hünig base, alkylhexamethyldisilazanes
  • the invention also relates to this process for the preparation of the compounds of the general formula I and the new intermediates of the general formulas B, C, BC and ABC including all stereoisomers of these compounds and also mixtures thereof.
  • Free hydroxyl groups in I, A, B, C, AB, ABC can be further functionally modified by etherification or esterification, free carbonyl groups by ketaiization, enol ether formation or reduction.
  • the invention also relates to these processes for the preparation of the epothilone derivatives of the general formula.
  • 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, BMM, 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
  • intercalating substances e.g. from the class of anthracyclines such as
  • Doxo bicin or from the class of antrapyrazoles such as CI-941, > substances interacting with tubulin e.g. from the class of Vinka alkaloids such as Vincristine, vinblastine or from the taxane class such as Taxol,
  • growth factors e.g. PDGF, EGF, TGFb, EGF
  • Somatostatin, suramin, bombesin antagonists inhibitors of protein tyrosine kinase or protein kinases A or C such as e.g. Erbstatin, Genistein, Staurosporin, llmofosin, 8-CI-cAMP,
  • Anti-hormones from the class of anti-progestogens such as mifepristone, onapristone or from the class of anti-estrogens such as tamoxifen or from the class of anti-androgens such as cyproterone acetate Compounds inhibiting metastases, for example from the class of eicosanoids such as PG ⁇ '2, PGE-j, o-Cxo-PGE-] and their stable derivatives (for example iloprost, cicaprost, misoprostol).
  • Inhibitors of oncogenic RAS proteins which influence the mitotic signal transduction such as, for example, inhibitors of farnesyl protein transferase,
  • Natural or artificially produced antibodies which are directed against factors or their receptors which promote tumor growth such as, for example, the erbB2 antibody, the invention also relates to medicaments based on the pharmaceutically acceptable, i.e. in the doses used, non-toxic compounds of the general formula I, if appropriate together with the customary auxiliaries and carriers.
  • the compounds according to the invention can be processed into pharmaceutical preparations for enteric, percutaneous, parenteral or local application according to known galenical methods. They can be administered in the form of tablets, coated tablets, gel capsules, granules, suppositories, implants, injectable sterile aqueous or oily solutions, suspensions or emulsions, ointments, creams and gels.
  • the active ingredient (s) can be combined with the auxiliaries commonly used in galenics, e.g. Gum arabic, talc, starch, mannitol, methyl cellulose, lactose, surfactants such as tweens or myrj, magnesium stearate, aqueous or non-aqueous vehicles, paraffin derivatives, wetting, dispersing, emulsifying, preserving agents and flavoring agents for flavor correction (e.g. essential oils).
  • auxiliaries commonly used in galenics e.g. Gum arabic, talc, starch, mannitol, methyl cellulose, lactose, surfactants such as tweens or myrj, magnesium stearate, aqueous or non-aqueous vehicles, paraffin derivatives, wetting, dispersing, emulsifying, preserving agents and flavoring agents for flavor correction (e.g. essential oils).
  • the invention thus also relates to pharmaceutical compositions which contain at least one compound according to the invention as active ingredient.
  • One dose unit contains about 0.1-100 mg of active ingredient (s).
  • the dosage of the compounds according to the invention in humans is about 0.1-1000 mg per day.
  • Example 1f The solution of 570 mg (1.55 mmol) of the compound shown in Example 1f is reacted analogously to Example 1e and, after workup and purification, 410 mg (1.06 mmoi, 68%) of the title compound is isolated as a colorless oil.
  • Example 1 h 4 [2-methyl-1 - (tert-butyidiphenylsilyloxy) prop-2-yl] -2,2-dimethyl- [1, 3] dioxane
  • the solution of 100 mg (0.212 mmol) of the compounds shown in Example 1 e in 2.5 ml of anhydrous acetone is mixed with 78.9 mg of copper (II) sulfate, a spatula tip of p-toluenesulfonic acid monohydrate and under an atmosphere of dry argon stirred for 16 hours at 23 ° C.
  • Variant II 320 mg (0.88 mmol) of the compound shown in Example 1 g are reacted analogously to Example 1 h; variant I and, after workup and purification, 234 mg (0.548 mmol, 62%) of the title compound are isolated.
  • Variant III 320 mg (0.88 mmol) of the compound shown in Example 1 g are reacted analogously to Example 1 h; variant I and, after workup and purification, 234 mg (0.548 mmol, 62%) of the title compound are isolated.
  • the organic phase is separated off, the aqueous phase is extracted several times with n-hexane, the combined organic extracts are washed with water and dried over magnesium sulfate. The residue obtained after filtration and removal of solvent is reacted further without purification.
  • Example 1 m (4S) -4- (2-ethyl-3-oxopent-2-yl) -2,2-dimethyl- [1,3] dioxane
  • the solution of 850 mg (3.93 mmol) of a mixture the compounds shown in Example 11 in 63 ml of anhydrous dichloromethane are mixed with molecular sieve (4A, approx. 80 spheres), 690 mg of N-methylmorpholino-N-oxide, 70 mg of tetrapropylammonium perruthenate and stirred for 16 hours at 23 ° C.
  • This solution is added under nitrogen via a reverse frit to a solution consisting of 17.8 g of hexamethyidisilazane in 140 ml of tetrahydrofuran with 73.5 ml of a 1.6 M solution of butyllithium in hexane at -60 ° C (10 minutes stirring time) and 23.3 g (4R, 5S ) -4-methyl-5-phenyl-3-propionyl-2-oxazolidinone in 62 ml of tetrahydrofuran (30 minutes stirring time). The mixture is left to stir at -60 ° C.
  • Example 1q (2S) -2-Methyl-6- (tert-butyidimethylsilyioxy) hexanoic acid ethyl ester
  • a solution of 10.5 g of the ester prepared according to Example 1 p in 200 ml of ethyl acetate is mixed with 1 g of 10% palladium-on-carbon and stirred for 3 hours at 22 ° C in a hydrogen atmosphere.
  • the catalyst is then filtered off, washed well with ethyl acetate and the filtrate is concentrated in vacuo.
  • the residue thus obtained is purified by chromatography on silica gel. With hexane / 0-10% ether, 9.95 g of the title compound is obtained as a colorless oil.
  • the crude product obtained is dissolved in 80 ml of toluene. 5 g of Dowex® (activated, acidic) are added and the mixture is boiled under reflux for one hour. The Dowex® is then filtered off and the filtrate is concentrated in vacuo. The crude product obtained (7.61 g) is used in the next stage without purification.
  • the residue obtained after filtration and removal of solvent is purified by chromatography on fine silica gel using a gradient system composed of n-hexane and ethyl acetate. 6.46 g (11.4 mmol, 83%) of the titanium compound are isolated as a colorless oil.
  • Example 1 ao (3S, 6R, 7S, 8S, 12E / Z.15S.16E) -17- (2-methyl-4-thiazolyi) -5-oxo-4,4,6,8,13.16-hexamethyi-heptadeca-12, 16-diene-1, 3,7,15-tetraol
  • Example 1 ap (3S, 6R, 7S, 8S, 12E / Z, 15S, 16E) -17- (2-methyl-4-thiazolyl) -4,4,6,8,13,16-hexamethyi- 1,3 , 7,15-tetrakis - [[dimethyl- (1, 1-dimethylethyl) siiyi] oxy] -heptadeca-12,16-dien-5-one
  • camphor-10-sulfonic acid 179 mg are added at 0 ° C. under argon to a solution of 735 mg of the silyl ether prepared above in a mixture of 8 ml of dichloromethane and 8 ml of methanol, and the mixture is allowed to warm to 22 ° C. and is stirred for a further 1.5 hours.
  • 0.6 ml of triethylamine is added, poured into a saturated sodium hydrogen carbonate solution and extracted several times with dichloromethane.
  • the organic phase is dried over sodium sulfate and, after filtration, concentrated in vacuo.
  • the residue thus obtained is chromatographed on silica gel cleaned. With hexane / 0-20% ethyl acetate, 527 mg of the title compound is obtained as a colorless oil.
  • Example 1s Analogously to Example 1s, 150 mg of the title compound A prepared in Example 1r are reacted. 81 mg of the titanium compound are obtained as a colorless oil.
  • Example 1au Analogously to Example 1au, 81 mg of the compound prepared above are reacted. 75 mg are obtained after column chromatography, which are again purified by preparative thick-layer chromatography with hexane / 10% ethyl acetate.
  • Example 2 Analogously to Example 2, 15 mg of the compound prepared in Example 3 are reacted. The purification is carried out only by preparative thick layer chromatography.

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Abstract

L'invention concerne les nouveaux dérivés d'épothilone de la formule générale (I) où les substituants Y, Z, R<1a>, R<1b>, R<2a>, R<2b>, R<3>, R<4a>, R<4b>, D-E, R<5>, R<6>, R<25>, R<7>, R<8> et X ont la signification donnée dans la description. Les nouveaux composés interagissent avec la tubuline en stabilisant les microtubuli formés. Ils sont en mesure d'agir de façon spécifique en phase sur la division cellulaire et conviennent au traitement de tumeurs malignes, par exemple, d'un carcinome de l'ovaire, de l'estomac, du côlon, du poumon, de la tête et du cou, d'un adénocarcinome, d'un mélanome malin et d'une leucémie lymphocytaire aigue et myélocytaire aigue. Ils conviennent également à la thérapie anti-angiogénèse et au traitement de maladies inflammatoires chroniques (psoriasis, arthrite). On peut les appliquer sur des matériaux polymères ou les introduire dedans pour éviter les proliférations cellulaires incontrôlées sur des implants médicaux et pour améliorer la tolérance de ces implants médicaux. On peut utiliser les composés selon l'invention, seuls ou en combinaison avec d'autres principes et classes de substances utilisables en thérapie tumorale pour obtenir respectivement des actions additionnelles ou des effets de synergique.
PCT/EP1999/004915 1998-06-30 1999-06-30 Derives d'epothilone, leur procede de production, produits intermediaires et leur utilisation pharmaceutique Ceased WO2000000485A1 (fr)

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DE19830060A DE19830060A1 (de) 1998-06-30 1998-06-30 Epothilon-Derivate, Verfahren zu deren Herstellung, Zwischenprodukte und ihre pharmazeutische Verwendung
DE19830060.3 1998-06-30
DE19923001A DE19923001A1 (de) 1999-05-13 1999-05-13 Epothilon-Derivate, Verfahren zu deren Herstellung, Zwischenprodukte und ihre pharmazeutische Verwendung
DE19923001.3 1999-05-13

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