EP1161430A2 - Derives d'epothilone, leur procede de production et leur utilisation pharmaceutique - Google Patents

Derives d'epothilone, leur procede de production et leur utilisation pharmaceutique

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Publication number
EP1161430A2
EP1161430A2 EP00920433A EP00920433A EP1161430A2 EP 1161430 A2 EP1161430 A2 EP 1161430A2 EP 00920433 A EP00920433 A EP 00920433A EP 00920433 A EP00920433 A EP 00920433A EP 1161430 A2 EP1161430 A2 EP 1161430A2
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EP
European Patent Office
Prior art keywords
methyl
dione
dihydroxy
ethenyl
pyridyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00920433A
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German (de)
English (en)
Inventor
Ulrich Klar
Werner Skuballa
Bernd Buchmann
Wolfgang Schwede
Michael Schirner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
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Filing date
Publication date
Priority claimed from DE1999107480 external-priority patent/DE19907480A1/de
Priority claimed from DE19954229A external-priority patent/DE19954229A1/de
Application filed by Schering AG filed Critical Schering AG
Publication of EP1161430A2 publication Critical patent/EP1161430A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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

Definitions

  • Epothilone derivatives processes for their preparation and their pharmaceutical
  • 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 al. 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
  • R 4 is hydrogen, C ⁇ -C ⁇ rj- alkyl, aryl, C7-C20- aralkyl,
  • R 5 is hydrogen, Ci-Cio-alkyl, aryl, C 7 -C 2 o-aralkyl,
  • R6, R7 each represent a hydrogen atom, together an additional bond or an oxygen atom
  • R8 is a methyl group or hydrogen, and at the same time R ⁇ a and Rlb together for a trimethylene group, R ⁇ for a phenyl or
  • Nitrogen atom oxidized, 2-pyridyl radical are available, including all possible stereoisimers and mixtures thereof.
  • alkyl groups R 4 and R ⁇ straight or branched chain alkyl groups with 1-20 carbon atoms are to be considered, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. -Butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl.
  • the alkyl groups R 4 and R-> can be perfluorinated or substituted by 1-5 halogen atoms, hydroxyl groups, C 1 -C 4 alkoxy groups, C 1 -C 4 aryl groups (which are replaced by 1-
  • Aryl radicals R 4 and R ⁇ are substituted and unsubstituted carbocyclic or heterocyclic radicals having one or more heteroatoms, such as, for example, phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl, the single or multiple can be substituted by halogen, OH, O-alkyl, CO2H, CO -alkyl, -NH 2 , -NO 2 , -N3, -CN, -C-C 2 o-alkyl, C! -C 20 -acyl, C! -C 20 acyloxy
  • Heteroatoms in the heteroaryl residues can be oxidized; for example, the thiazole ring can be in the form of the N-oxide.
  • the nitrogen atom in the 2-pyridyl, 2-methyl-4-thiazolyl or 2-methyl-4-oxazolyl radical representing X can be in the form of the N-oxide.
  • the aralkyl groups in R 4 and R ⁇ may contain up to 14 carbon atoms in the ring, preferably 6 to 10 and in the alkyl chain 1 to 8, preferably 1 to 4 atoms.
  • suitable aralkyl radicals are benzyl, phenylethyl, naphthylmethyl, naphthylethyl, furylmethyl, Thienylethyl, pyridylpropyl.
  • the rings can be mono- or polysubstituted by halogen, OH, O-alkyl, CO 2 H, CO 2 -alkyl, -NO 2 , -N 3 , -CN, Ci-C ⁇ alkyl, -C-C 20 acyl ,
  • the presentation of the new epothilone derivatives is based on the linking of three partial fragments A, B and C (DE 197 51 200.3, filing date November 13, 1997 and the corresponding PCT / EP98 / 05064).
  • A represents a Cl-C6 fragment (epothilone counting) of the general formula
  • Rl3a j Rl4a hydrogen, S ⁇ 2 ⁇ alkyl, S ⁇ 2-aryl, S ⁇ 2-aralkyl or together one
  • Rl3b Rl4b hydrogen, -CC 2 o-alkyl, aryl, C 7 -C 20 aralkyl,
  • Rl 5a j Rl 5b are the same or different and are hydrogen, CjC-io-alkyl, aryl, C7-
  • R 3 ' is hydrogen, C 1 -C ⁇ 0 alkyl, aryl, C 7 -C o aralkyl,
  • R 5 ' is hydrogen, C 1 -C 6 -alkyl, aryl, C7-C20-aralkyl,
  • HHHH V is an oxygen atom, two alkoxy groups OR ⁇ , a C2-Ci Q-alkylene- ⁇ , ⁇ -dioxy group, which can be straight-chain or branched or H / ORl ",
  • W is an oxygen atom, two alkoxy groups OR19, a C2-C ⁇ o-alkylene- ⁇ , ⁇ - dioxy group, which can be straight-chain or branched or H / OR 8,
  • Rl 6, Rl 8 independently of one another hydrogen or a protective group PGl R! " 7, R19 independently of one another are C j -C20 alkyl.
  • R ° is hydrogen, -CC20-alkyl, aryl, C7-C20-aralkyl, which can all be substituted, and R '' is a hydrogen atom,
  • R20 is a hydrogen atom or a protective group PG ⁇
  • R2 is a hydroxy group, halogen, a protected hydroxy group OPG 3
  • U is an oxygen atom, two alkoxy groups OR ⁇ 3 , a C2-Cjo-alkylene- ⁇ , ⁇ -dioxy group, which can be straight-chain or branched, H / OR ⁇ or one
  • R23 for a C 1 -C 20 -alkyl radical
  • R ° for hydrogen or a protective group PG 3 , RIO, R l 1 are the same or different and are hydrogen, a C1-C2O-alkyl, aryl, C7-C20-aralkyl radical or
  • Rl 0 and R together with the methylene carbon atom together represent a 5- to 7-membered carbocyclic ring.
  • alkyl groups Ria ', R lb', R 2a ', R 2b', R 3 ', R 4', R 5 ', R 8', R 9, R 10, R ll, R 12, R 13b,
  • alkyl groups Ria ', Rlb', R 2a ', R 2b', R 3 ', R 4', R 8 ', R 9, R 10, R ll, R 12, R 13b,
  • R 14b, R 15a, R 15b, 17 and ( j R 23 can be perfluorinated or substituted by 1-5
  • Halogen atoms hydroxyl groups, C1 -C4 alkoxy groups, C (3-C ⁇ 2 aryl groups (through 1-
  • R 15a and ( J R 15b come substituted and unsubstituted carbocyclic or heterocyclic radicals with one or more heteroatoms such as phenyl, naphthyl, furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, thiazolyl, the single or multiple can be substituted by halogen, OH, O-alkyl, CO 2 H, CO2
  • Alkyl -NH 2 , -NO 2 , -N3, -CN, -C-C () alkyl, -C-C 2 o-acyl, -C-C 2 o-acyloxy groups, in
  • 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 R ia ', R l ', R2a ', R 2b', R 3 ', R 4', R 5 ', R 8', R 9, R 10, R l 1, R 12 R 13b R 14b , R 15a and ( R 15b can contain up to 14 carbon atoms in the ring, preferably 6 to 10 and in the alkyl chain 1 to 8, preferably 1 to 4 atoms.
  • suitable aralkyl radicals are benzyl, phenylethyl, naphthylmethyl, naphthylethyl, Furylmethyl, thienylethyl, pyridylpropyl
  • the rings can be mono- or polysubstituted by O
  • protective groups PG are alkyl- and / or aryl-substituted silyl, C1 - C 2 o-alkyl, C4-C7-cycloalkyl, which can additionally contain an oxygen atom in the ring, aryl, C7-C o-aralkyl, Cj -C 2 o-acyl and aroyl to name.
  • 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 radicals from the corresponding alkyl and silyl ethers, such as, for example, methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert.-butyldimethylsilyl, tert.-butyldiphenyldiphenyl -, 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 1 and R 2 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 Ria and Rlb is preferably 2, 3 or 4.
  • the C 2 -C ] 0-alkylene- ⁇ , ⁇ -dioxy group which is possible for X is preferably an ethyl enketal or neopentyl ketal group.
  • the present invention provides, for example, the following variants of the compounds of the general formula I:
  • R 4 and R5 primarily denote a methyl group.
  • the invention particularly relates to the compounds
  • the partial fragments (synthesis building blocks) of the general formula A can be easily removed a) a pantolactone of the general formula Ha
  • Ria ', Rlb' each represent a methyl group or b) a dialkyl malonate of the general formula XXVIII
  • Alkyl independently of one another a Cj-C o- alkyl-, C -Cjo-cycloalkyl- or C4- 20-
  • Alkylcycloalkylrest mean.
  • pantolactone (A-II) The free hydroxyl group of pantolactone (A-II) is according to those known to those skilled in the art
  • the protective groups PG 4 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, tribenzylsilylsilyl, tribenzylsilylsilyl, tribenzylsilylsilylsilylsilylsilylsilylsilylsilylsilylsilyl and tribenzylsilylsoles -, benzyl, para-nitrobenzyl, para-methoxybenzyl, formyl, acetyl, propionyl, isopropionyl,
  • Preferred protective groups are those which can be cleaved under acidic reaction conditions, such as e.g. the methoxymethyl, tetrahydropyranyl, tetrahydrofuranyl,
  • the tetrahydropyranyl radical is particularly preferred.
  • the protected lactone A-III is reduced to lactol A-IN.
  • 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.
  • the methods known to the person skilled in the art such as e.g. the olefination according to Tebbe, the Wittig or Wittig / Horner reaction, the addition of an organometallic compound with elimination of water.
  • the Wittig reaction using methyltriarylphosphonium halides such as e.g.
  • Methyl triphenylphosphonium bromide with strong bases such as e.g. n-butyllithium, potassium tert-butoxide, sodium ethoxide, sodium hexamethyldisilazane; n-butyllithium is preferred as the base.
  • Protective groups which can be cleaved under the action of fluoride such as e.g. the trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl,
  • Anti-Markovnikov water is added to the double bond in A-VI.
  • the methods known to the person skilled in the art such as the reaction with boranes, their subsequent oxidation to the corresponding boric acid esters and their saponification.
  • Preferred boranes are e.g. 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.
  • Hydrogen peroxide is preferably used as the oxidizing agent, and alkali metal hydroxides such as e.g. Sodium hydroxide.
  • the protective group PG 4 introduced under step a) is then cleaved by 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.
  • acids such as para-toluenesulfonic acid, para-toluenesulfonic acid-pyridinium salt, camphorsulfonic acid in alcoholic solutions, preferably in ethanol or Isopropanol.
  • a common protection of both alcohol functions of the mono-protected 1,3-diol in A-VII is by direct ketalization with a carbonyl compound of the general formula R ⁇ . CO-Rl ⁇ b, or by transketalization with a ketal of the general formulas, Rl5a_ C (OC 2 H 5 ) 2 -Rl5b, Rl5a_c (OC 2 H 4 ) 2 -Rl 5b , Rl5a_c (OCH 2 C (CH 3 ) 2 CH 2 O) -Rl 5b wherein each Rl ⁇ > a and R 15b have the meanings given above, possible under acid catalysis.
  • Suitable acids are the acids already mentioned under step f), preference is given to the use of para-toluenesulfonic acid, optionally with the addition of copper (II) or cobalt (II) salts such as copper (II) sulfate.
  • Protection of both alcohol functions of the 1,3-diol in A-VIII is by direct ketalization with a carbonyl compound of the general formula or by transketalization with a ketal of the general formulas, R 15a. C (OC 2 H 4 ) 2-Rl 5b , R 15 -C (OCH2C (CH 3 ) 2 CH2 ⁇ ) -Rl 5 b wherein Rl 5a and R i 5 b each have the meanings given above, under acid catalysis.
  • Transketalization with 2,2-dimethoxypropane is preferred.
  • Suitable acids are the acids already mentioned under step f); preference is given to using camphorsulfonic acid.
  • the protective group PG ⁇ introduced under step d) is then cleaved by the processes 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 e.g. para-toluenesulfonic acid, para-toluenesulfonic acid pyridinium salt, camphorsulfonic 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
  • catalytic amounts of acids such as e.g. para-toluenesulfonic acid, para-toluenesulfonic acid pyridinium salt, camphors
  • 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.
  • X represents a halogen
  • R ⁇ a ' and R ⁇ b' radicals each have the meanings given above.
  • Magnesium and zinc are preferred as divalent metal, and chlorine, bromine and iodine are preferred as halogen X.
  • Step m (A-XII ### A-XIII): The oxidation of the secondary alcohol in A-XII to the ketone A-XIII takes place according to the conditions mentioned under step k). Oxidation with N-methyl-morpholino-N-oxide using tetrapropylammonium perruthenate is preferred.
  • R ⁇ a ' in A-XIII is hydrogen
  • R ⁇ a' which has the abovementioned meanings, with the exception of hydrogen.
  • R ⁇ a' which has the abovementioned meanings, with the exception of hydrogen.
  • X represents a halogen.
  • the halogen X is preferably chlorine, bromine and iodine.
  • Step k conditions mentioned.
  • the oxidation method according to Swern is preferred.
  • Step p (A-XV ### A-XVI):
  • X represents a halogen and the radicals R ⁇ 'and R ⁇ b' 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.
  • A-XVII The free hydroxy group in A-XVII is protected by the methods known to those skilled in the art.
  • the protective groups PG ⁇ which are known to the person skilled in the art, as already mentioned above for PG 4 in step a (A-II ### A-III), are suitable.
  • Protecting groups which can be cleaved under basic or hydrogenolytic reaction conditions are preferred, such as, for example, benzyl, para-nitrobenzyl, acetyl, propionyl, butyryl, benzoyl radical.
  • the benzoyl radical is particularly preferred.
  • the protection group PG ⁇ 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, preference is given to saponification with carbonates in alcoholic solution, such as, for example, potassium carbonate in methanol, saponification with aqueous solutions of alkali metal hydroxides such as lithium hydroxide or sodium hydroxide using organic, water-miscible solvents such as methanol, ethanol, tetrahydrofuran or dioxane.
  • Step k conditions mentioned. Oxidation with N-methylmorpholino-N-oxide using tetrapropylammonium perruthenate and the method according to are preferred
  • Examples include oxidation according to Jones, oxidation with potassium permanganate, for example in an aqueous system composed of tert-butanol and sodium dihydrogenphosphate, oxidation with sodium chlorite in aqueous tert-butanol, optionally in the presence of a chlorine scavenger, e.g. 2-methyl-2-butene.
  • the oxidation of the aldehyde in A-XXI to the ester A-XXII, in which Rl ⁇ b has the abovementioned meanings and is not hydrogen, can be carried out, for example, with pyridinium dichromate and the desired alcohol HO-Rl ⁇ b in an inert solvent such as dimethylformamide.
  • Step k conditions mentioned. Oxidation with N-methylmorpholino-N-oxide using tetrapropylammonium perruthenate and the method according to are preferred
  • Step y (A-XXIII ### A-XXJN): The oxidation of the aldehyde A-XXIII to the carboxylic acid or its ester A-XXIV takes place according to the conditions already described under w).
  • the protective group PG ⁇ introduced under step d) is split as described under step i.
  • a free hydroxyl group in A-XXIX is selectively protected by methods known to those skilled in the art.
  • protection group PG ⁇ come those known to those skilled in the art
  • Protecting groups as already mentioned above for PG 4 in step a (A-II ### A-III), are also in question. Protective groups containing silicon are preferred.
  • Step af (A-XXX ### A-XXXI): The oxidation of the remaining primary hydroxyl group in A-XXX to the aldehyde A-XXXI takes place according to the conditions mentioned under step k). Preference is given to oxidation with N-methylmorpholino-N-oxide using tetrapropylammonium per-ruthenate, the use of pyridinium chlorochromate, pyridinium dichromate and the Swern method.
  • the aldehydes A-XXXI are reacted with an ester of acetic acid chGl ⁇ C (O) CH3, in which chGl is a chiral auxiliary group, in the sense of an aldol reaction.
  • the compounds chG ⁇ C (O) CH3 are used in optically pure form in the aldol reaction.
  • the type of chiral 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.
  • Suitable chiral auxiliary groups chGl-OH are, for example, optically pure 2-phenylcyclohexanol, pulegol, 2-hydroxy-l, 2,2-triphenylethanol, 8-phenylmenthol.
  • 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 chGl-OH by processes known to the person skilled in the art.
  • Carbonates in alcoholic solution such as e.g. Potassium carbonate in methanol, aqueous solutions of alkali hydroxides such as Lithium hydroxide or sodium hydroxide using organic water-miscible solvents such as e.g. Methanol, ethanol, tetrahydrofuran or dioxane.
  • the chiral auxiliary group can also be removed reductively.
  • the enantiomerically pure compounds of type A-VIII or ent-A-VIII are obtained.
  • the reduction can be carried out by the methods known to the person skilled in the art.
  • suitable reducing agents are diisobutyl aluminum hydride and complex metal hydrides such as lithium aluminum hydride.
  • the compounds A-VIII or ent-A-VIII can be converted into compounds of the types A-XIII or ent-A-XIII as described above.
  • compounds of type A-XXXIII or ent-A-XXIII can be converted into compounds of type A-XII or ent-A-XXII according to the methods described above.
  • the sequence can also be carried out without using a chiral auxiliary group chGl.
  • racemic mixtures of compounds of the rac-A-VIII or rac-A-XXXIII type are then obtained via the corresponding racemic precursors.
  • These mixtures can in turn be prepared by the processes known to those skilled in the art for resolving racemates, e.g. Chromatography on chiral columns. The synthesis can also be continued with the racemic mixtures.
  • the present invention thus also relates to a process for the preparation of the compounds of the general formula A, which is characterized in that a) a pantolactone of the general formula Ha or b) a malonic acid dialkyl ester of the general formula XXVIII is used as the starting product.
  • the present invention thus also relates to the new Cl-C6-epothilone building blocks of the general formula A '
  • R 2a, R 2b are hydrogen, -C ⁇ alkyl, aryl, C7-C 20 aralkyl,
  • R 3 is hydrogen, OR 3a , X, OSO 2 R 3b ,
  • R 3a is hydrogen or together with R 2a is a - (CH 2 ) n group or
  • R 6a, R 6b are the same or different and C j -Cg alkyl, Cß-Ci o-aryl, or together a - (CH 2 ) 0 group, o 3 to 6,
  • R6 can additionally assume the meaning of hydrogen, 4a, 4b are the same or different and hydrogen, C -C ⁇ Q- alkyl, Cy-C 2 o-
  • R 5a, R 5b are the same or different and are hydrogen, C] -C ⁇ Q- alkyl, C7-C 2 o-
  • Aralkyl or together a - (CH 2 ) p group, p 2 to 5, 5c hydrogen, including all stereoisomers and mixtures thereof, and etherified or esterified free hydroxyl groups in R 2 and R 3 , free carbonyl groups in A and
  • R 2 is ketalized, converted into an enol ether or reduced, and free acid groups in A in whose salts can be converted with bases,
  • R 3 OR 3 and 3a hydrogen or a protective group PG
  • R 4a, R 4b are the same or different and are hydrogen, CI-CJQ-alkyl, C7-C 2 Q-
  • R ⁇ a , R ⁇ b are the same or different and are hydrogen, CI -CJ O- alkyl, C7-C 2 Q-
  • Aralkyl or together a - (CH 2 ) p group, p 2 to 5, including all stereoisomers and mixtures thereof, and free carbonyl groups in I can be ketalized, easily by reacting a compound of general formula II
  • X is a chlorine or bromine atom, and the 2-oxazolidinone ring is either (4R, 5S) - or
  • R 4a, 4b are the same or different and are hydrogen, Cj-Cio-alkyl, C7-C20-
  • R 5a, 5b are the same or different and are hydrogen, C] -C ⁇ o-alkyl, C7-C20-
  • Aralkyl or together a - (CH2) p group, p 2 to 5, mean,
  • reaction of a compound of the general formula II with a compound of the general formula III succeeds after converting the compound of the general formula II into a metal enolate by inserting a metal or metal salt into the carbon-halogen bond of the compound of the general formula II.
  • Suitable metals or metal salts are generally all metals or metal salts known to the person skilled in the art which are suitable for a Reformatzky reaction (see, for example, A. Mosatzky reaction 1989, 571-590). According to the invention, chromium (II) chloride is preferably used.
  • alkyl groups R a , R4b, 5a un ( j R 5b s ⁇ nc ⁇ straight or branched chain alkyl groups with 1 to a maximum of 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, Pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl.
  • the alkyl groups R 4a , R 4 b, R 5a and R 5b can be perfluorinated or substituted by 1-5 halogen atoms, hydroxyl groups, C -C4-alkoxy groups and Cg-C ⁇ aryl groups (which can be substituted by 1-3 halogen atoms ).
  • the aralkyl groups in R 4a , R b, R 5a and R 5b may 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- to trisubstituted by halogen, OH, O-alkyl, NH 2 , CO 2 H, CO 2 alkyl, -NO 2 , -N 3 , -CN, -C-C 2 o-alkyl, Ci -
  • Protective groups PG are all radicals known to those skilled in the art as such protective groups. Preference is given here to silyl-containing protective groups, such as, for example, the trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl radical.
  • Halogen means fluorine, chlorine, bromine and iodine.
  • the compounds of general formula II required for the process according to the invention are by acetylation of (4R, 5S) - or (4S, 5R) -4-methyl-5-phenyl-2-oxazolidinone with bromine or chloroacetyl chloride in the presence of a strong base , such as n-butyllithium, accessible.
  • III can be bought or is easy to manufacture.
  • Fig. 1 The starting material is (substituted) malonic ester
  • secondary amine preferably piperidine or morpholine or R "and R 7 independently of one another represent a straight-chain or branched Ci-Cg-alkyl group.
  • Section of the epothilone framework are used according to modified epothilone derivatives.
  • a great advantage of the process according to the invention is also that the chiral auxiliary used (4R, 5S) or (4S, 5R) -4-methyl-5-phenyl-2-oxazolidinone after it has been split off from the protected compound of the general easily retrieve Formula IV and reuse it in the synthesis without loss of optical induction.
  • the building blocks obtained in this way are suitable for aldocondensation with an epothilone building block which has a carbonyl function on C-7 (epothilone counting), as is the case with the above-mentioned total syntheses of epothilone A and Epothilon B is the case.
  • the protective groups PG ⁇ which are known to the person skilled in the art, as already mentioned above for PG 4 in step a (A-II ### A-III), are suitable.
  • Protective groups containing silicon which can be cleaved under acidic reaction conditions or using fluoride, such as, for example, the trimethylsilyl, triethylsilyl, tert.-butyldimethylsilyl, tert.-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl radical, are preferred.
  • the tert-butyldimethylsilyl 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 anhydrides by the methods known to the person skilled in the art.
  • Trifluoromethanesulfonate is preferred as the leaving group LG.
  • the compound B-IV is with the enolate of a carbonyl compound of the general
  • chG ⁇ can be a simple alkoxy group or a chiral auxiliary group, alkylated by the methods known to the person skilled in the art.
  • the enolate is formed by the action of strong bases such as e.g. Lithium diisopropylamide, lithium hexamethyldisilazane produced at low temperatures.
  • strong bases such as e.g. Lithium diisopropylamide, lithium hexamethyldisilazane produced at low temperatures.
  • chG ⁇ -H B-VI
  • suitable chiral, optically pure and inexpensive alcohols such as Pulegol, 2-phenylcyclohexanol, 2-hydroxy-l, 2,2-triphenyl ethanol, 8-phenylmenthol or inexpensive, inexpensive, reactive, NH-containing compounds such as e.g.
  • B-XVII obtained enantiomerically pure. If chG ⁇ -H (B-VI) is an achiral alcohol such as Ethanol used, so you get the racemic compounds rac-B-VII to rac-B-XVII.
  • the group chG ⁇ represents one of the chiral auxiliary groups mentioned under step c, this is recovered by transesterification of B-VII into an alkyl ester of the general formula B-VIII.
  • the transesterification takes place according to the methods known to the person skilled in the art. Transesterification with simple alcohols such as e.g. Methanol or ethanol in the presence of appropriate titanium (IV) alcoholates.
  • Step e (B-VIII ### B-LX):
  • the ester in B-VIII is reduced to alcohol B-IX.
  • Suitable reducing agents are the reducing agents known to the person skilled in the art, such as, for example, aluminum hydrides such as, for example, lithium aluminum hydride or diisobutyl aluminum hydride.
  • the reaction takes place in an inert solvent such as diethyl ether, tetrahydrofuran, toluene.
  • the carbonyl group in B-VII can be reduced directly to the alcohols of the general formula B-LX under the conditions mentioned under step e).
  • the chiral auxiliary component chG ⁇ -H can also be recovered here.
  • Preferred protective groups are those which can be cleaved under acidic reaction conditions, such as e.g. the methoxymethyl, tetrahydropyranyl, tetrahydrofuranyl,
  • the tetrahydropyranyl radical is particularly preferred.
  • the protective group PG ⁇ introduced under step a) is then split according to 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 e.g. para-toluenesulfonic acid, para-toluenesulfonic acid pyridinium salt, camphorsulfonic 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
  • catalytic amounts of acids such as e.g. para-toluenesulfonic acid, para-toluenesulfonic acid pyridinium salt, camphorsulfonic
  • the oxidation of the primary alcohol in B-XI to the aldehyde of the general formula B-XII 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, 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. Oxidation according to Swern and with N-methylmorpholino-N-oxide using tetrapropylammonium perruthenate is preferred.
  • the alcohol B-XIII is oxidized to the ketone of the general formula B-XIN by the processes mentioned under h). Oxidation with ⁇ -methyl-morpholino- ⁇ -oxide using tetrapropylammonium perruthenate is preferred.
  • Protection group PG ⁇ be provided.
  • 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, tribenzylsilyl, triisopropylsilyl radical.
  • the tert-butyldiphenylsilyl radical is particularly preferred.
  • the protective group PG ⁇ introduced under step f) is cleaved according to the procedure described under step g).
  • the alcohol B-XVI is oxidized to the aldehyde of the general formula B-XVII by the processes mentioned under h). Swern oxidation is preferred.
  • the compounds of 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, for example, lithium diisopropylamide, lithium hexamethyl disilazane at low temperatures and with 3-halogeno 1-propyne, preferably 3-bromo-l-propyne to give compounds of the general formula B-XIX.
  • strong bases such as, for example, lithium diisopropylamide, lithium hexamethyl disilazane at low temperatures and with 3-halogeno 1-propyne, preferably 3-bromo-l-propyne to give compounds of the general formula B-XIX.
  • the ester B-XIX is reduced to the alcohol B-XX by the methods described in step e), preferably using diisobutylaluminum hydride.
  • the hydroxyl group in B-XX can, according to the conditions mentioned under a), with a
  • Protection group PG ⁇ be provided.
  • 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, tribenzylsilyl, triisopropylsilyl radical.
  • the tert-butyldimethylsilyl radical is particularly preferred.
  • Step r (B-XXI ### B-XIII):
  • the acetylene B-XXI can be deprotonated by the methods known to those skilled in the art and the acetylide obtained can be reacted with carbonyl compounds of the general formula B-XXII, in which R ⁇ 'has the meaning given above, to give an alcohol of the general formula XIII.
  • Alkyl alkali compounds such as butyl lithium or other strong bases such as alkali hexamethyl disilazanes or lithium diisopropyl amide are suitable for deprotonation. N-Butyllithium is preferred.
  • racemic compound rac-B-XIX can be obtained with a chiral, optically obtainable
  • Alcohol chG ⁇ -OH by the methods known to the person skilled in the art, for example the process mentioned under step d), to transesterify to a mixture of the diastereomeric esters B-XLXa and separate using simple chromatographic methods.
  • suitable chiral alcohols are pulegol, 2-phenylcyclohexanol, 2-hydroxy-l, 2,2-triphenylethanol and 8-phenylmenthol.
  • Step t (B-XIXa ### B-XX and ent-B-XX):
  • the diastereomerically pure esters B-XIXa can each be reduced to the alcohols B-XX or ent-B-XX according to the process described in step e, it being possible to recover the auxiliary component chG - ⁇ - OH described in step s.
  • racemic compound rac-B-XX can be obtained with a chiral, optically obtainable
  • Acid chG 4 -C02H its ester, anhydride or acid halide by the methods known to the person skilled in the art to a mixture of the diastereomeric esters XXa and separate with simple chromatographic methods.
  • suitable chiral acids are malic acid, tartaric acid or their derivatives.
  • the diastereomerically pure esters B-XXa can in each case be reduced to the alcohols B-XX or ent-B-XX by the process described in step e, or saponified by the methods known to the person skilled in the art, the auxiliary component described in step u being used in the latter case chG 4 -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).
  • Protection group PG 2 are those known to the person skilled in the art
  • Preferred protective groups are those which can be cleaved under the action of fluoride, but are stable under weakly acidic reaction conditions, such as e.g. the tert-butyldiphenylsilyl, tert-butyldimethylsilyl or triisopropylsilyl radical.
  • the tert-butyldiphenylsilyl and the tert-butyldimethylsilyl radical are particularly preferred.
  • Lactone C-III is reduced to lactol C-IV by the methods known to those skilled in the art. Modified reactants are suitable as reducing agents
  • Aluminum hydrides such as Diisobutyl aluminum hydride.
  • the reaction takes place in an inert solvent such as e.g. Toluene, preferably at low temperatures (-20 to -
  • R ⁇ Represents halogen and R ⁇ 'has the meanings given above.
  • Magnesium and zinc are preferred as divalent metal, and chlorine, bromine and iodine are preferred as halogen X.
  • the secondary hydroxy group is then optionally also protected by known methods known to those skilled in the art.
  • Protective groups PG ⁇ and PG * I are the protective groups known to the person skilled in the art, as already mentioned above for PG 4 in step a (A-II ### A-III). Preference is given to protecting groups which can be split selectively under weakly acidic reaction conditions in the presence of the protective group PG10, which is introduced from building block A into the synthesis of the compound of the general formula I, such as, for example, trimethylsilyl, triethylsilyl, tert. Butyldimethylsilyl residue. The tert-butyldimethylsilyl radical is particularly preferred.
  • the oxidation of the secondary alcohol in C-VI to the ketone C-VII 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. ⁇ -Methyl-morpholino- ⁇ -oxide in the presence of suitable catalysts such as e.g. Tetrapropylammonium perruthenate in inert solvents. Swern oxidation is preferred.
  • the ketone is prepared by the methods known to the person skilled in the art, for example using an alcohol HOR2 or a C2-Cjo-alkylene ⁇ , ⁇ -diols ketalized under acid catalysis.
  • the cleavage preferably takes place under weakly acidic conditions, e.g. by reaction with dilute organic acids in inert solvents. Acetic acid is preferred.
  • 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 carried out from the bromide by substitution e.g. according to Finkelstein with sodium iodide in acetone.
  • the direct conversion of the hydroxyl group into the iodide is also possible, e.g. using elemental iodine, imidazole and triphenylphosphine in dichloromethane.
  • the triphenylphosphonium halides are based on the halides C-X according to the processes known to the person skilled in the art
  • the reaction of the corresponding halides with triphenylphosphine in solvents such as toluene or benzene is suitable for the preparation of the phosphonium salts.
  • the phosphonates can be prepared, for example, by reacting the halides CX with a metalated dialkyl phosphite. The metalation is usually done with strong bases such as butyllithium.
  • the phosphine oxides can be prepared, for example, by reacting the halides CX with metallized diphenylphosphine and subsequent oxidation. Strong bases such as butyllithium are also suitable for the metalation. The subsequent oxidation to the phosphine oxide can then take place, for example, with dilute aqueous hydrogen peroxide solution.
  • R 1 is a methyl group
  • R 2 is a tert-butyldimethylsilyl or benzyl radical
  • R 3 is an O-tert-butyldimethylsilyl radical
  • X is an oxygen atom or a (2-methylthiazole-4 -yl) methylene rest, only in an optical purity of approx. 80% ee.
  • the chemical yields of the process according to the invention are significantly higher than those of the Schinzer et al. yields described process.
  • the present invention thus relates to a process for the preparation of the compounds of the general formula C, which is characterized in that
  • Optically pure D - (+) - or L - (-) - malic acid is preferably used.
  • the invention also relates to the intermediate compounds of the general formulas V, VI and VI 'occurring in the process (hereinafter referred to as VI ")
  • PC-2 + H stand for a hydrogen atom or a protective group PG 2 .
  • these compounds are prepared by adding a compound of the general formula IV
  • PG * has the meaning given in the general formula C, opening the lactol ring, an organometallic compound of the general formula
  • R 1 has the meaning given in the general formula C, and
  • Y represents an alkali metal atom or MZ, where M is a divalent metal atom and Z is a halogen atom,
  • Lithium is preferred as the alkali atom.
  • magnesium and zinc are preferred for the divalent metal atom; as
  • Halogen atom is primarily chlorine, bromine and iodine.
  • the present invention also relates to the new C13-C16 epothilone building blocks of the general formula C.
  • R 1 is hydrogen, CC 20 - alkyl, aryl, C 7 -C 0 aralkyl, which can all be substituted
  • R 2 is hydrogen or a protective group PG 1 ,
  • R 3 is a hydroxy group, halogen, a protected hydroxy group OPG 2
  • Phosphonate residue P (O) (OQ) 2 (Q Cj-C] o-alkyl or phenyl) or a
  • X is an oxygen atom, two alkoxy groups OR 4 , a C 2 -C] 0 -alkylene- ⁇ , ⁇ -dioxy group, which can be straight-chain or branched, H / OR 5 or one
  • R 4 is a C, -C 20 -alkyl radical
  • R 5 represents hydrogen or a protective group PG 3
  • R 6 , R 7 are identical or different and, for hydrogen, a CC 2 o-alkyl, aryl, C 7 -C 2 o-aralkyl radical or R 6 and R 7 together with the methylene carbon atom together for a 5- to 7- membered carbocyclic ring, mean, not at the same time
  • R 1 is a methyl group
  • R 2 is a tert-butyldimethylsilyl or benzyl radical
  • R 3 is a
  • O-tert-butyldimethylsilyl radical and X is a (2-methylthiazol-4-yl) methylene radical or
  • R 1 is a methyl group
  • R 2 is a tert-butyldimethylsilyl radical
  • R 3 is a
  • Triphenylphosphoniumiodidrest and X can be a (2-methylthiazol-4-yl) methylene residue.
  • the first disclaimer excludes those compounds that Schinzer et al. were produced by a process other than the process according to the invention (Chem. Eur. J. 1996, 2, No. 11, 1477-1482 and Angew. Chem. 1997, 109, No. 5, 543-544).
  • the second disclaimer takes into account that of K. C. Nicolaou et al. in Nature, vol. 387, 1997, 268-272, mentioned (5E, 3S) - [3 - [[((l, l-dimethylethyl) dimethylsilyl] oxy] -4-methyl-5- (2-methylthiazole-4- yl) -pent-4-en-l-yl] triphenylphosphonium iodide.
  • PG 1 , PG 2 and PG 3 from the group of the substituents methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert.-butyldimethylsilyl, tert.-butyldiphenylsilylsilyl, tribenzylsilyl, tribenzylsilyl, tribenzylsilyl , Benzyl, para-nitrobenzyl, para-methoxybenzyl, acetyl, propionyl, butyryl and benzoyl radicals are selected, in particular PG 1 is a tert-butyldiphenylsilyl, tert-butyldimethylsilyl or triisopropylsilyl and in particular PG 2 is a tert-butyldimethylsilyl, acety
  • Protective groups PG 4 and PG 5 are all protective groups already mentioned above for PG 1 , PG 2 and PG 3 .
  • R 1 a ', R2b ' ? R3 ? R4a_ R4b_ R ⁇ , R13 I R14 D, E, V and Z have the meanings already mentioned and PG 14 represents a hydrogen atom or a protective group PG are obtained from the fragments A and B described above by the process shown in Scheme 8.
  • 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,
  • the compound C in which R21 has the meaning of a Wittig salt and any additional carbonyl groups which may be present are protected, is converted by a suitable base, e.g. Deprotonated n-butyllithium, lithium diisopropylamide, potassium tert-butoxide, sodium or lithium hexamethyldisilazide and reacted with a compound AB, in which V has the meaning of an oxygen atom.
  • a suitable base e.g. Deprotonated n-butyllithium, lithium diisopropylamide, potassium tert-butoxide, sodium or lithium hexamethyldisilazide
  • Step e (ABC ###!): The compounds ABC in which R ⁇ 3 is a carboxylic acid CO2H and R 20 a
  • Hydrogen atom is converted according to the methods known to those skilled in the art for the formation of large macrolides to give compounds of the formula I in which Y has the meaning of an oxygen atom.
  • the method described in "Reagents for Organic Synthesis, Vol. 16, p 353" is preferred using 2,4,6-trichlorobenzoic acid chloride and suitable bases such as e.g. Triethylamine, 4-dimethylaminopyridine, sodium hydride.
  • Represents hydrogen atom can preferably be converted using triphenylphosphine and azodiesters such as, for example, diethyl azodicarboxylate to give compounds of the formula I in which Y has the meaning of two hydrogen atoms.
  • CH2 ⁇ S ⁇ 2Aryl or CH2 ⁇ S ⁇ 2Aralkyl and R 20 represents a hydrogen atom can be cycled after deprotonation with suitable bases such as sodium hydride, n-butyllithium, 4-dimethylaminopyridine, Hünig base, alkylhexamethyl disilazanes to give compounds of the formula I in which Y has the meaning of two hydrogen atoms .
  • suitable bases such as sodium hydride, n-butyllithium, 4-dimethylaminopyridine, Hünig base, alkylhexamethyl disilazanes to give compounds of the formula I in which Y has the meaning of two hydrogen atoms .
  • Free hydroxyl groups in I, A, B, C, AB, ABC can be etherified or
  • the invention relates to all stereoisomers of these compounds and also theirs
  • 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 O platinum complexes such as Cisplatin, carboplatin, O intercalating substances e.g. from the class of anthracyclines such as
  • 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, O DNA topoisomerase inhibitors such as e.g. Camptothecin, etoposide, topotecan,
  • Somatostatin Somatostatin, suramin, bombesin antagonists, O inhibitors of protein tyrosine kinase or protein kinases A or C, such as, for example, erbstatin, genistein, staurosporin, llmofosin, 8-CI-cAMP, O anti-hormones from the class of antigenic agents such as, for example, mifepristone,
  • Cicaprost, Misoprostol O inhibitors of oncogenic RAS proteins that influence mitotic signal transduction, such as inhibitors of farnesyl protein transferase, O natural or artificially produced antibodies that are against factors or their
  • Receptors that promote tumor growth are directed, such as 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 customary in galenics, such as gum arabic, talc, starch, mannitol, methyl cellulose, lactose, surfactants such as tweens or myrj, magnesium stearate, aqueous or non-aqueous vehicles, paraffin derivatives, wetting agents, dispersing agents and emulsifiers -, preservatives and flavorings for flavor correction (eg essential oils) are mixed.
  • 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 approximately 0.1-100 mg of active ingredient (s).
  • the dosage of the compounds according to the invention in humans is about 0.1-1000 mg per day.
  • the 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 14 (4S) -4- (3-Methyl-2-oxo-prop-3-yl) -2,2-dimethyl- [1,3] dioxane
  • Example 11 Analogously to Example 11, 420 mg (2.08 mmol) of the compounds shown in Example 13 are reacted. After working up and purification, 388 mg (1.94 mmol, 93%) of the title compound are isolated as a colorless oil.
  • Example 10 Analogously to Example 10, 450 mg (2.42 mmol) of the compound shown in Example 9 are reacted using n-propyl magnesium bromide. After working up and purification, a total of 244 mg (1.06 mmol, 44%) of a separable mixture of the epimeric title compounds and 191 mg of the title compound described in Example 8 are each isolated as a colorless oil.
  • Example 15 Analogously to Example 11, 230 mg (1.00 mmol) of the compounds shown in Example 15 are reacted. After working up and purification, 185 mg (0.81 mmol, 81%) of the title compound are isolated as a colorless oil.
  • H-NMR (CDCI3): ⁇ 0.88 (3H), 1.04 (3H), 1.12 (3H), 1.22-1.37 (1H), 1.31 (3H),
  • Example 8 Analogously to Example 8, 1.22 g (2.44 mmol) of the compound shown in Example 20 is reacted and, after workup and purification, 593 mg (2.27 mmol, 93%) of the title compound are isolated as a colorless oil.
  • Example 21 Analogously to Example 9, 570 mg (2.18 mmol) of the compound shown in Example 21 are reacted and, after working up, 780 mg of the title compound is isolated as a yellow oil, which is reacted further without purification.
  • Example 10 Analogously to Example 10, 780 mg (max. 2.18 mmol) of the crude product shown in Example 22 is reacted and, after working up and purification, 468 mg (1.62 mmol, 74%) of the epimeric title compounds are isolated as a colorless oil.
  • Example 8 Analogously to Example 8, 1.20 g (2.53 mmol) of the compound shown in Example 25 is reacted and, after workup and purification, 518 mg (2.19 mmol, 87%) of the title compound is isolated as a colorless oil.
  • Example 9 Analogously to Example 9, 500 mg (2.12 mmol) of the compound shown in Example 26 are reacted and, after working up, 715 mg of the title compound is isolated as a yellow oil, which is reacted further without purification.
  • Example 28 (2S, 4S) -4 - ((3RS) -2-methyl-3-hydroxy-pent-2-yl) -2-phenyl- [1,3] dioxane
  • 715 mg (max. 2.12 mmol) of the crude product prepared according to Example 27 is reacted and, after workup and purification, 440 mg (1.66 mmol, 79%) of the epimeric title compounds are isolated as a colorless oil.
  • Example 11 Analogously to Example 11, 435 mg (1.65 mmol) of the compound shown in Example 28 are reacted and, after workup and purification, 410 mg (1.56 mmol, 95%) of the title compound are isolated as a colorless oil.
  • Example 9 Analogously to Example 9, 450 mg (1.97 mmol) of the compound shown in Example 31 are reacted and, after working up, 678 mg of the title compound is isolated as a yellow oil, which is reacted further without purification.
  • Example 11 Analogously to Example 11, 386 mg (1.51 mmol) of the compound shown in Example 33 is reacted and, after workup and purification, 376 mg (1.48 mmol, 98%) of the title compound is isolated as a colorless oil.
  • Example 20 In analogy to Example 20, 1.00 g (2.59 mmol) of the compound shown in Example 6 is converted into 50 ml of toluene using cyclopentanone and, after workup and purification, 997 mg (2.20 mmol, 85%) is isolated Title compound as a colorless oil.
  • Example 35 Analogously to Example 8, 997 mg (2.20 mmol) of the compound shown in Example 35 is reacted and, after workup and purification, 415 mg (1.94 mmol, 88%) of the title compound is isolated as a colorless oil.
  • Example 9 Analogously to Example 9, 400 mg (1.87 mmol) of the compound shown in Example 36 are reacted and, after working up, 611 mg of the title compound is isolated as a yellow oil, which is reacted further without purification.
  • Example 38 Analogously to Example 11, 348 mg (1.44 mmol) of the compound shown in Example 38 are reacted and, after workup and purification, 332 mg (1.38 mmol, 96%) of the title compound are isolated as a colorless oil.
  • Hexane is produced in absolute tetrahydrofuran lithium diisopropylamide.
  • a solution of 1 1, 2 g (1 /? - frat7s) -2-phenylcyclohexyl acetate in 100 ml of absolute tetrahydrofuran is then added at -78 ° C. and the mixture is stirred for 30 minutes at this temperature.
  • Example 44 Analogously to Example 44, 700 mg (1.57 mmol) of the compound B prepared according to Example 43 are reacted and, after workup and purification, 250 mg (0.91 mmol, 58%) of the title compound are isolated.
  • the 1 H-NMR spectrum is congruent with that described in Example 44.
  • Example 44 Analogously to Example 44, 500 mg (1.12 mmol) of a mixture of the compounds A and B prepared according to Example 43 are reacted and, after workup and purification, 190 mg (0.69 mmol, 62%) of the title compound are isolated.
  • Example 45 Analogously to Example 45, 190 mg (0.69 mmol) of the compound prepared according to Example 48 are reacted and, after workup and purification, 171 mg (0.54 mmol, 79%) of the title compound are isolated.
  • Example 43 Analogously to Example 1, 460 mg (1.03 mmol) of the compound shown in Example 43 are reacted and, after workup and purification, 398 mg (0.75 mmol, 73%) of the title compound are isolated as a colorless oil.
  • the reaction product can be converted into the aldehyde by oxidation analogously to Example 9, analogously to Example 10 using an organometallic compound such as XMgCHRSaR 5 ⁇ for example
  • Example 9 Analogously to Example 9, 5.0 g (23.3 mmol) of the compound shown in Example 3 is reacted and, after working up, 6.1 g of the title compound is isolated as a colorless oil, which is reacted further without purification.
  • Example 10 Analogously to Example 10, 6.1 g (max. 23.3 mmol) of the crude product shown in Example 52 are reacted and, after workup and purification, 1.59 g (6.56 mmol, 28%) of the non-polar diastereomer and 1 , 67 g (6.89 mmol, 30%) of the polar diastereomer each as a colorless oil.
  • 0.17 ml of a 30% hydrogen peroxide solution are added at 0 ° C. to a solution of 190 mg of the silyl ether prepared in Example lc) in 2.5 ml of a mixture of tetrahydrofuran and water in a ratio of 4: 1.
  • a solution of 15.8 mg of lithium hydroxide in 0.83 ml of water is then added, and the reaction mixture is stirred at 25 ° C. for 3 hours.
  • a solution of 208 mg of sodium sulfite in 1.24 ml of water is then added and the mixture is extracted with 10 ml of methylene chloride.
  • the above methylene chloride phase is washed with 5N hydrochloric acid and then this aqueous phase is extracted three times with 10 ml of ethyl acetate. After drying over sodium sulfate and filtration, the mixture is concentrated in vacuo and an additional amount of crude product is obtained.
  • the combined residues thus obtained are purified by chromatography on silica gel.
  • Example 2 Analogously to Example 1, from 2.79 g (5.9 mmol) of the compound described under 3b), 49 g (80%) of the title compound and 941 mg of recovered (4S, 5R) -4-methyl-5-phenyloxazolidine 2-one received.
  • the title compound and the chiral auxiliary to be recovered can be separated by chromatography (analogously to Example 1) or fractional crystallization and then, if desired, purified by chromatography.
  • 1 H-NMR (CDCI3): ⁇ 0.09 (3H), 0.19 (3H), 0.90 (9H), 1.08 (3H), 1.70 - 2.00 (3H),
  • the NMR spectrum is congruent with Example 3.
  • the stereochemistry in position 3 can be controlled by the choice of stereochemistry at C4 and C5 of the chiral auxiliary 4-methyl-5-phenyl-2-oxazolidone.
  • intermediate 1 b The structure of intermediate 1 b) was confirmed by an X-ray structure analysis.
  • a solution of 77.2 g of diisopropylamine in 270 ml of tetrahydrofuran is added to 473 ml of a 1.6 M solution of butyllithium in hexane at -15 ° C. to 0 ° C. under nitrogen and then stirred for 30 minutes.
  • a solution of 85.0 g of ethyl cyclobutane carboxylate in 170 ml of tetrahydrofuran is then added dropwise at -70 ° C., and after 1.5 hours a solution of 78.9 g of 3-bromo-1-propyne in 190 ml of tetrahydrofuran is stirred and the mixture is stirred at -70 ° C.
  • This solution is added under nitrogen via a reverse frit to a solution consisting of 17.8 g of hexamethyldisilazane 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 11 2.07 g of the alcohol shown in Example 11 is oxidized analogously to Example 14 and, after working up and purification by chromatography, 2.09 g of the title compound is isolated as a colorless oil.
  • Example 18 2.13 g of the alcohol shown in Example 18 is oxidized in analogy to Example 14 and, after working up and chromatographic purification, 2.10 g of the title compound is isolated as a colorless oil.

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  • Organic Chemistry (AREA)
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  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
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Abstract

La présente invention concerne de nouveaux dérivés d'épothilone correspondant à la formule générale (I), dans laquelle: R4 représente hydrogène, alkyle C¿1?-C10, aryle, aralkyle C7-C20; R?5¿ représente hydrogène, alkyle C¿1?-C10, aryle, aralkyle C7-C20; R?6, R7¿ représentent chacun un atome d'hydrogène, et ensemble une liaison complémentaire ou un atome d'oxygène; R8 représente un groupe méthyle ou hydrogène; R?1a et R1b¿ représentent ensemble un groupe triméthylène et X représente un reste 2-pyridyle, 2-méthyl-4-thiazolyle ou 2-méthyl-4-oxazolyle; ou bien R?1a et R1b¿ représentent ensemble un groupe triméthylène, R2 représente un groupe méthyle, éthyle ou propyle et X représente un reste 2-pyridyle, 2-méthyl-4-thiazolyle ou 2-méthyl-4-oxazolyle; ou bien R?1a et R1b¿ représentent chacun un groupe méthyle, R2 représente un reste méthyle, éthyle ou propyle et X représente un reste 2-pyridyle, 2-méthyl-4-thiazolyle ou 2-méthyl-4-oxazolyle, l'atome d'azote et/ou de soufre dans X pouvant être présent sous forme oxydée et, lorsque R2 et R8 représentent chacun un reste méthyle, X ne pouvant être qu'un reste 2-pyridyle éventuellement oxydé au niveau de l'atome d'azote. L'invention concerne également tous les stéréoisomères possibles de ces dérivés et leurs mélanges. Ces nouveaux composés peuvent être utilisés pour la production de médicaments.
EP00920433A 1999-02-11 2000-02-11 Derives d'epothilone, leur procede de production et leur utilisation pharmaceutique Withdrawn EP1161430A2 (fr)

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DE1999107480 DE19907480A1 (de) 1999-02-11 1999-02-11 Epothilon-Derivate, Verfahren zu deren Herstellung und ihre pharmazeutische Verwendung
DE19907480 1999-02-11
DE19954229 1999-11-04
DE19954229A DE19954229A1 (de) 1999-11-04 1999-11-04 Epothilon-Derivate, Verfahren zu deren Herstellung und ihre pharmazeutische Verwendung
PCT/EP2000/001104 WO2000047584A2 (fr) 1999-02-11 2000-02-11 Derives d'epothilone, leur procede de production et leur utilisation pharmaceutique

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EA (1) EA200100833A1 (fr)
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ES2315399T3 (es) * 2001-08-23 2009-04-01 Novartis Ag Analogos de epotilona ciclobutilo y ciclopropilo.
ATE452896T1 (de) 2002-03-12 2010-01-15 Bristol Myers Squibb Co C3-cyanoepothilonderivate
ATE476995T1 (de) * 2002-06-10 2010-08-15 Novartis Pharma Gmbh Epothilone enthaltende kombinationen und deren pharmazeutische verwendungen
CA2494536C (fr) * 2002-07-31 2011-10-04 Mercian Corporation Substance active d'un macrolide cyclique a 12 chainons
US20050215604A1 (en) * 2004-03-26 2005-09-29 Kosan Biosciences, Inc. Combination therapies with epothilones and carboplatin
EP1589011A1 (fr) * 2004-04-22 2005-10-26 Schering Aktiengesellschaft Nouveaux dérivés chiraux d'heptyne pour la préparation des epothilones et procédés pour leur préparation
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US8008256B2 (en) * 2006-05-01 2011-08-30 University Of Southern California Combination therapy for treatment of cancer
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CZ20012886A3 (cs) 2001-11-14
US20060040990A1 (en) 2006-02-23
BR0008206A (pt) 2002-02-19
WO2000047584A2 (fr) 2000-08-17
HUP0105330A2 (hu) 2002-05-29
CA2360952A1 (fr) 2000-08-17
KR20010094763A (ko) 2001-11-01
JP2002536450A (ja) 2002-10-29
NO20013900D0 (no) 2001-08-10
NO20013900L (no) 2001-10-11
HK1044946A1 (zh) 2002-11-08
YU57601A (sh) 2005-06-10
BG105803A (en) 2002-03-29
IL144370A0 (en) 2002-05-23
EA200100833A1 (ru) 2002-02-28
EE200100422A (et) 2002-12-16
CN1340053A (zh) 2002-03-13
MXPA01008148A (es) 2003-07-21
WO2000047584A3 (fr) 2000-12-28
PL350190A1 (en) 2002-11-18
US7001916B1 (en) 2006-02-21
AU4101800A (en) 2000-08-29

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