WO2011120886A1 - Procédé pour la préparation de (-)-englerine a et de ses analogues et intermédiaires - Google Patents

Procédé pour la préparation de (-)-englerine a et de ses analogues et intermédiaires Download PDF

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WO2011120886A1
WO2011120886A1 PCT/EP2011/054665 EP2011054665W WO2011120886A1 WO 2011120886 A1 WO2011120886 A1 WO 2011120886A1 EP 2011054665 W EP2011054665 W EP 2011054665W WO 2011120886 A1 WO2011120886 A1 WO 2011120886A1
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formula
compound
crc
halogen
protective group
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Antonio Maria Echavarren Pablos
Kian Molawi
Nicolás Pierre Robert DELPONT
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Institut Català D'investigació Química (Iciq)
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • 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
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/18—Bridged systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a enantioselective process for the preparation of (-)- englerin A and analogues thereof, as well as some intermediates useful in this preparation process.
  • (-)-Englerin A is a sesquiterpene diester isolated from the stem bark of the east African plant Phyllanthus engleri that has been shown to selectively inhibit the growth of renal cancer cell lines at the nanomolar level.
  • (-)-Englerin A was found to be 1 -2 orders of magnitude more potent than taxol against certain cancer cell lines.
  • WO 2009/088854 discloses the isolation of Englerin A and Englerin B from the root bark and stem bark of the plant Phyllanthus engleri Pax
  • the process of the invention provides a total synthesis of the mentioned compounds, that is easily scalable, without the need to obtain the mentioned compounds by isolation from natural sources such as from the root bark and stem bark or the plant Phyllanthus engleri.
  • Some of the intermediates employed in this process are novel compounds and are included as part of the invention.
  • the key feature of the preparation process of the present invention is the intermediate compound of formula (II)
  • compound of formula (II) of the present invention allows introducing firstly the desired moiety in C-6, and so later introduction of moieties in C-9 wearing a -OH group (such as it is required for preparing (-)-englerin A) can be carried out without the need of protecting such a group. Additionally, unlike the mentioned disclosures of the prior art, compound of formula (II) enables to easily functionalize in 3 steps at 2 positions (C-6 and C-9) using the chemistry of secondary alcohols known to the skilled in the art. Besides, compound of formula (II) is obtained in high overall yield from achiral, readily available and inexpensive starting materials.
  • an aspect of the present invention is the provision of a process for the preparation of a compound of formula (I)
  • R 1 is selected from the group consisting of cinnamoyl, cinnamyl, 3-phenylpropyl, 3-phenylpropanoyl, benzyloxy carbonyl, N-benzyl amino carbonyl, or N-benzyl amino thiocarbonyl, wherein the phenyl moiety is optionally substituted by a (CrC 6 )-alkyl, a (CrC 6 )-hydroxyalkyl, a (C-i-C 6 )- alkoxy, an halogen, or a nitro, and the alkyl and alkenyl moieties are optionally substituted by an halogen or a hydroxyl; and R 2 is selected from the group consisting of (CrC 5 )-alkylcarbonyl, hydroxyl-(CrC 5 )-alkylcarbonyl, hydroxyl-(CrC 6 )-alkyl, (CrC 6 )-alkoxycarbon
  • Another aspect of the present invention is the provision of a process for the preparation of a connpound of formula (II) as defined above, the process comprising the catalytic hydrogenation of a compound of formula (III)
  • Compound of formula (I) can be obtained by first transforming a compound of formula (II) into a compound of formula ( ⁇ )
  • R 1 and PG 1 are as defined above.
  • An additional aspect of the invention is the provision of a compound of formula (I) or of formula ( ⁇ ) as defined above, provided that in compound of formula (I) when R 1 is cinnamoyl optionally substituted in position 2' with halogen, wherein the phenyl moiety is optionally substituted by a (C-i-C 6 )- alkyl, a (CrC 6 )-hydroxyalkyl, a (CrC 6 )-alkoxy, an halogen, or a nitro; or R 1 is 3-phenylpropanoyl substituted in position 3' with halogen, hydroxy or (Ci-C 6 )- alkoxy and optionally substituted in position 2' with halogen, wherein the phenyl moiety is optionally substituted by a (CrC 6 )-alkyl, a (C-i-C 6 )- hydroxyalkyl, a (CrC 6 )-alkoxy, an halogen, or a
  • Another aspect of the invention relates to a compound of formula (I) or of formula ( ⁇ ) as defined above for use in the treatment of cancer, provided that in compound of formula (I) when R 1 is cinnamoyl optionally substituted in position 2' with halogen, wherein the phenyl moiety is optionally substituted by a (CrC 6 )-alkyl, a (CrC 6 )-hydroxyalkyl, a (CrC 6 )-alkoxy, an halogen, or a nitro; or R 1 is 3-phenylpropanoyl substituted in position 3' with halogen, hydroxy or (CrC 6 )-alkoxy and optionally substituted in position 2' with halogen, wherein the phenyl moiety
  • the invention provides further compounds having a common basic scaffold to the ones already known in the art. Nevertheless, the known compounds have the disadvantage of being obtainable only either by isolation from the plant Phyiianthus engleri or by subsequent transformation of the naturally occurring englerin A or englerin B, namely by an hemisynthetic process.
  • the proposed R 1 and R 2 groups of the compounds of the invention having similar physical or chemical properties than the corresponding substituents on (-)-englerin A, provide to the final compound a potent citotoxicity activity against cancer cell lines.
  • Ar is a phenyl group, optionally substituted with a Ci-C 6 alkyl, Ci-Ce hydroxyalkyl, Ci-Ce alkoxy, halo, or nitro;
  • X is O, NH, or S;
  • R 5 and R 6 are independently a Ci-Ce alkyl;
  • R 4 is isopropyl or isopropylidenyl;
  • "a" is a single bond or a double bond; when “a” is a double bond, R 7 is hydrogen, and R 8 is halo or H; when “a” is a single bond, R 7 is selected from the group consisting of halo, hydroxy, or Ci-Ce alkoxy and R 8 is halo or H; and
  • R 9 is Ci-Ce alkyl or hydroxy Ci-Ce alkyl;
  • a further aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least a therapeutically effective quantity of the compound of formula (I) or of formula ( ⁇ ) as defined above as the active principle, and one or more pharmaceutically acceptable excipients or carriers.
  • Scheme I illustrates the global process for the preparation of a compound of formula (I) as defined above.
  • PG 1 and PG 2 are suitable ether protective groups
  • R 1 and R 2 are different substituents providing ester, ether, carbonate, carbamate or thiocarbamate derivatives in the corresponding positions in any combination
  • R 3 is hydrogen or PG 1 .
  • R 1 is selected from the group consisting of cinnamoyl, cinnamyl, 3-phenylpropyl, 3-phenylpropanoyl, benzyloxy carbonyl, N-benzyl amino carbonyl, or N-benzyl amino
  • R 2 is selected from the group consisting of (C-1-C5)- alkylcarbonyl, hydroxyl-(CrC 5 )-alkylcarbonyl, hydroxyl-(CrC 6 )-alkyl, (Ci-C 6 )- alkoxycarbonyl, and (Ci-C 6 )-alkylaminocarbonyl.
  • ether protective groups of alcohols are given in T.W. Greene et al., "Protective Groups in Organic Synthesis", Chapter 2, "Protection for the hydroxyl group, including 1 ,2- and 1 ,3-diols” John Wiley & Sons, 3rd ed., New York 1999, pp. 17-148.
  • Ether protected hydroxyl groups can be prepared by procedures known in the art, and can be easily removed when the desired reaction is complete (ibid. T.W. Greene).
  • the alcohol protective group is a benzyl, p-methoxybenzyl, methoxymethyl or silyl ether protective group.
  • the protective group is a silyl ether protective group. Suitable silyl ether protective groups for the alcohol moieties are selected from those known in the art.
  • the silyl ether protective group is selected from trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylhexylsilyl (TDS), tert-butvldimethvlsilvl (TBS), tert-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-Q-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), di-tert-butylmethylsilyl (DTBMS), tris(trimethylsilyl)silyl, 2- hydroxystyryl)dimethylsilyl (HSDMS), 2-hydroxystyryl)diisopropylsilyl (HSDIS), tert-butylmethoxyphenyls
  • the silyl ether protective group is selected from triethylsilyl (TES), triisopropylsilyl (TIPS), and tert-butvldimethvlsilvl (TBS).
  • TES triethylsilyl
  • TIPS triisopropylsilyl
  • TBS tert-butvldimethvlsilvl
  • Reactivity (both formation and cleavage) of silyl ethers, used as protective groups for alcohols, can be modulated by a suitable choice of sustituents on the silicon atom. (ibid. T.W. Greene, pp. 1 13-148).
  • compound of formula (I) as defined above can be obtained by formation of an ester, ether, carbonate, carbamate, or
  • first, formation of the corresponding derivative of the unprotected secondary alcohol is carried out.
  • another ester, ether, carbonate, carbamate, or thiocarbamate moiety can be formed on the new secondary alcohol moiety.
  • the process comprises: a) formation of an ester, ether, carbonate, carbamate, or thiocarbamate of the secondary alcohol of the compound of formula (II) as defined above, to obtain a compound of formula ( ⁇ )
  • esters can be obtained by reaction of the hydroxyl group through the use of an acid chloride or acid anhydride and a suitable base, such as pyridine or triethylamine.
  • Ethers can be obtained, for example, through the Williamson ether synthesis by reaction with the corresponding organohalide in the presence of a suitable base, such as a carbonate base or potassium hydroxide, or a phase transfer catalyst, and in a suitable solvent, such as acetonitrile and ⁇ , ⁇ -dimethylformamide.
  • Carbonates can be obtained either similarly to the process for the preparation of esters mentioned above but using the corresponding chloroformiate, or by reaction of the alcohol with the corresponding organohalide under a CO 2 atmosphere in the presence of additives such as 18-crown-6, Kl or tetrabutylammonium iodide (TBAI).
  • Carbamates can be obtained by reaction of an alcohol with the corresponding isocyanate, while thiocarbamates can be similarly obtained by reaction of the alcohol with the corresponding isothioacyanate.
  • R 2 is acetyl, glycoloyl, hydroxyethyl, ethoxycarbonyl, or ethylaminocarbonyl.
  • R 1 is a cinnamoyl group and R 2 is a glycoloyl group (i.e., the obtained compound is englerin A) or an acetyl group (i.e., the obtained compound is englerin B monoacetate).
  • compound of formula (I) as defined above is any one from englerin A, englerin B monoacetate, 2'-chloroenglerin A, 2'-chloro-3'- hydroxydihydroenglerin A, 2',3'-dichlorodihydroenglerin A, and 2'-chloro-3'- ethoxydihydroenglerin A.
  • compound of formula (II) can be prepared by an iridium-catalysed hydrogenation of a compound of formula (III)
  • PG 1 is an ether protective group.
  • the protective group is a silyl ether protective group.
  • PG 1 is tert- butyldimethylsilyl.
  • the reaction can be carried out with an iridium catalysts as disclosed in B. Wustenberg et al ., Adv. Synth. Catal. 2008, vol . 350, pp. 174-178, and W.-J. Lu et al . Adv. Synth. Catal. 2010, vol . 352, pp. 103-107, such as the ones depicted b low:
  • the iridium catalyst is [lr(Py)(PCy 3 )(COD)][BAr F ]. This catalyst allowed to obtain a separable 1 :1 mixture of compound of formula (II) and its 4,5-diastereomer in quantitative yield, unlike other catalyst.
  • Compound of formula (II) and its 4,5-diastereomer can be separated by conventional separation methods, such as fractional crystallization or chromatography, as will become apparent to those skilled in the art.
  • the reaction is carried out in the presence of an appropriate solvent.
  • solvents include, for instance, (CrC 3 )-chlorine containing solvents such as dichloromethane, (C 6 -C 8 )-aromatic hydrocarbons such as toluene and xylene, ethers such as dietylether, dimethoxyethane, and tetrahydrofuran, and mixtures thereof. Conversion of compound of formula (IV) to compound of formula (III)
  • PG 1 is as defined above, can be carried out by reduction of a compound of formula (IV) with an appropriate reagent system yielding a compound of formula (III).
  • the reaction is carried out in the presence of an appropriate solvent.
  • Appropriate solvents include, for instance (C 6 -C 8 )- aromatic hydrocarbons such as toluene or xylene, ethers such as dietylether, dimethoxyethane, and tetrahydrofuran, and mixtures thereof.
  • the reduction reaction can be carried out by methods known to those skilled in the art, such as by reaction with a lower valent tungsten halide derivative.
  • the appropriate reagent system is WCI 6 and / BuLi.
  • Compounds of formula (IV) can be prepared by reaction of a compound of formula (V) with a chromium(VI) oxidizing agent to yield a compound of formula (IV)
  • the chromium(VI) oxidizing agent is selected from the group consisting of chromium trioxide-pyridine complex (Collins reagent), pyridinium chlorochromate, pyridinium dichromate and chromium trioxide-2,5- di methyl pyrazole complex.
  • the oxidizing agent is chromium trioxide-2,5-dimethylpyrazole complex, this providing unexpectedly high yields.
  • the corresponding epoxy ketone (compound of formula (IV)) may also be formed along with the desired epoxy alcohol (compound of formula (IV), as is the case when the reaction is carried out with Collins reagent).
  • the epoxy ketone can be quantitatively transformed into compound of formula (IV) with NaBH 4 and CeCI 3 .
  • the oxidizing agent is chromium trioxide-pyridine complex, the process further comprising the step of reducing a compound of formula (IV)
  • Reduction can be carried out by Luche reduction, namely with lanthanoid chlorides such as CeCI 3 and NaBH 4 , the reaction being quantitative.
  • PG 1 and PG 2 are a silyl ether protective group.
  • Example 17, and 46% in Example 20 have further advantages, such as reduction of the number of synthetic steps, higher purity of the compound obtained after the gold-catalyzed cycloaddition, and easier purification of the same due to the more polar nature of the starting compounds. Accordingly, in a preferred embodiment of the
  • R 3 is hydrogen.
  • R 3 is hydrogen and PG 2 is a silyl ether protective group, such as triethylsilyl.
  • the cationic gold(l)-complex is selected from the ones disclosed in cf. C. H. M. Amijs et al., J. Org. Chem. 2008, vol. 73, p. 7724, such as
  • (S)-3,7-dimethyloct-6-en-1 -yn-3-ol (X) can be prepared from natural geraniol (XI) in three steps according to the procedure of D. K. Mohapatra et al., Eur. J. Org. Chem. 2007, pp. 5059-5063, with an overall yield of 81 % and an enantiomeric ratio (er) of 95:5.
  • Compound of formula (IX) can be obtained by protection of propargylic alcohol (X), for instance as a silyl ether, and subsequent oxidative cleavage of the olefin.
  • compound of formula (VII) can be optionally protected to obtain a compound of formula (VI") (i.e. a compound of formula (VI) wherein R 3 is an ether protective group).
  • the protective group is a silyl ether group.
  • the process for the preparation of the present invention includes the deprotection reaction of several intermediates to remove the protective group.
  • the ether protective groups of the alcohol moieties can be removed by procedures known in the art (ibid. T.H. Greene).
  • the conditions for carrying out the deprotection reaction depend on the protective group used. For instance, when triethylsilyl, tnisopropylsilyl, or tert-butyldimethylsilyl are used, the deprotection reaction can be carried out with tetra-n-butylammonium fluoride (TBAF).
  • TBAF tetra-n-butylammonium fluoride
  • cleavage of silyl ethers protective groups can be modulated by a suitable choice of substituents on the silicon atom.
  • Electron-withdrawing substituents on the silicon atom increase its susceptibility toward basic hydrolysis, but decrease it sensitivity toward acid.
  • the stability towards acid increases in the order TMS (1 ) ⁇ TES (64) ⁇ TBS (20,000) ⁇ TIPS (700,000) ⁇ TBDPS (5,000,000), and the stability toward base increases in the order TMS (1 ) ⁇ TES (10-100) ⁇ TBS (20,000)- TBDPS (20,000) ⁇ TIPS (100,000).
  • Selective cleavage of numerous silyl derivatives is available in T. D. Nelson, et al., Synthesis, 1996, pp. 1031 -1069.
  • the process of the invention can be carried out in sequential steps isolating the intermediates obtained, or alternatively, some of the steps of the present invention can be carried out in one pot, without isolation of any intermediate compound.
  • R 1 is selected from the group consisting of cinnamoyl, cinnamyl, 3-phenylpropyl, 3-phenylpropanoyl, N-benzyl amino carbonyl, or N- benzyl amino thiocarbonyl, wherein the alkyl and alkenyl moieties are optionally substituted by an halogen or a hydroxyl;
  • R 2 is selected from the group consisting of (CrC 5 )-alkylcarbonyl, hydroxyl-(CrC 5 )-alkylcarbonyl, hydroxyl-(CrC 6 )-alkyl, (CrC 6 )-alkoxycarbonyl, and (C-i-C 6 )- alkylaminocarbonyl; and
  • PG 1 is an ether protective group; provided that in compound of formula (I) when R 1 is cinnamoyl optionally substituted in position 2
  • the invention also relates to the use of the new compounds of formula (I) or of formula ( ⁇ ), wherein R 1 is selected from the group consisting of cinnamoyl, cinnamyl, 3-phenylpropyl, 3-phenylpropanoyl, benzyloxy carbonyl, N-benzyl amino carbonyl, or N-benzyl amino thiocarbonyl, wherein the alkyl and alkenyl moieties are optionally substituted by an halogen or a hydroxyl; R 2 is selected from the group consisting of (CrC 5 )-alkylcarbonyl, hydroxyl- (CrC 5 )-alkylcarbonyl, hydroxyl-(CrC 6 )-alkyl, (CrC 6 )-alkoxycarbonyl, and (d- C 6 )-alkylaminocarbonyl; and PG 1 is an ether protective group; provided that in compound of formula (I) when R 1 is cinnam
  • the cancer can be any suitable cancer, for example, renal cancer, ovarian cancer, breast cancer, CNS cancer, leukemia, prostate cancer, non-small cell lung cancer, colon cancer, or melanoma, particularly renal cancer, CNS cancer, breast cancer, and ovarian cancer.
  • the compound of formula (I) or of formula ( ⁇ ) of the present invention is administered in a dose sufficient to treat the cancer.
  • doses are known in the art. Suitable doses and dosage regimens can be determined by
  • the present method can involve the administration of about 0.1 g to about 50 mg of at least one compound of the invention per kg body weight of the individual. For a 70 kg patient, dosages of from about 10 ig to about 200 mg of the compound of the invention would be more commonly used, depending on a patient's physiological response, e.g., as determined by measuring cancer-specific antigens or other measurable parameters related to the tumor load of a patient.
  • compositions comprising at least a therapeutically effective quantity of the compound of formula (I) or of formula ( ⁇ ) (provided that in compound of formula (I) when R 1 is cinnamoyl optionally substituted in position 2' with halogen, or R 1 is 3-phenylpropanoyl substituted in position 3' with halogen, hydroxy or (CrC 6 )-alkoxy and optionally substituted in position 2' with halogen, then R 2 is not (CrC 5 )-alkylcarbonyl or hydroxyl-(Ci-C 5 )- alkylcarbonyl, and with the proviso that compound of formula (I) is not englerin A or englerin B monoacetate) as the active principle, and one or more pharmaceutically acceptable excipients or carriers also form part of the invention.
  • the pharmaceutically acceptable carrier is preferably one that is chemically inert to the compound of the invention and one that has no detrimental side effects or toxicity under the conditions of use.
  • the choice of carrier will be determined in part by the particular compound chosen, as well as by the particular method used to administer the composition.
  • compositions of the present invention can be administered orally, parentally, or topically.
  • TES triflate (7.1 ml_, 8.3 g, 31 mmol) was added dropwise to a solution of (S)- 3,7-dimethyloct-6-en-1 -yn-3-ol (X), 4.0 g, 26 mmol) and NEt 3 (6.6 ml_, 4.8 g, 47 mmol) in dichloromethane (40 ml_) at 0 °C.
  • the mixture was stirred for 3 h at room temperature before being quenched with sat. aq. NH 4 CI solution.
  • the aqueous phase was extracted twice with dichloromethane.
  • the combined organic layers were washed with brine, dried over MgSO 4 and concentrated in vacuo. Chromatographic purification (hexane) of the crude material yielded the corresponding silyl ether as a colorless oil (7.0 g, 100%).
  • EXAMPLE 7 (1 S.3aR4S.5R7R-7-lsopropyl-1 ,4-dimethyl-1 ,2,3.3a.4.5.6.7- octahvdro-4,7-epoxyazulene-1 ,5-diol (V")
  • a TBAF solution (1 .0 M in THF, 1 .47 mL, 1 .47 mmol) was added to a solution of the compound obtained in Example 6 (450 mg, 1 .23 mmol) in THF (10 mL) at 0 °C. After stirring the mixture at room temperature for 10 h the reaction was stopped by addition of a sat. aq.
  • Example 8 A solution of the compound obtained in Example 8 (100 mg, 0.273 mmol) in dichloromethane (2 mL) was added at once and the mixture was stirred for 1 h at room temperature. Then the suspension was filtered through SiO 2 and the solvents were evaporated.
  • NEt 3 (4.5 ⁇ , 33 ⁇ ) and 2,4,6-trichlorobenzoyl chloride (1 .4 M in toluene, 10 ⁇ , 14 ⁇ ) were added to a stirred solution of englerin B (5.1 mg, 13 ⁇ ), TBDPS-protected glycolic acid (4.5 mg, 14 ⁇ ) and DMAP (3.2 mg, 26 ⁇ ) in toluene (0.5 ml) at 0 °C.
  • the resulting white suspension was stirred at room temperature for 1 h before being quenched by addition of sat. aq. NH4CI solution. Et2O was added and the layers were separated. The aqueous layer was extracted twice with Et 2 O. The combined organic extracts were washed with brine, dried over Na 2 SO 4 and concentrated in vacuo.

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Abstract

L'invention concerne un procédé pour la préparation de (-)-englerine A ainsi que des composés analogues de celle-ci, le procédé comprenant la transformation d'un composé de formule (II) dans laquelle PG1 est un groupe protecteur d'éther, par une séquence de réactions comprenant la déprotection ou la protection d'une ou plusieurs des fractions alcooliques et la formation d'un ester, éther, carbonate, carbamate ou thiocarbamate des fractions alcooliques, les différentes réactions étant réalisées dans un ordre quelconque. Certains des intermédiaires employés dans ce procédé sont des nouveaux composés et sont inclus comme partie de l'invention. L'invention concerne également de nouveaux composés analogues de la (-)-englerine A qui sont utiles dans le traitement du cancer ainsi que des compositions pharmaceutiques les comprenant.
PCT/EP2011/054665 2010-03-29 2011-03-28 Procédé pour la préparation de (-)-englerine a et de ses analogues et intermédiaires WO2011120886A1 (fr)

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WO2013106226A2 (fr) 2012-01-09 2013-07-18 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Méthodes de traitement ou de prévention de l'insulinorésistance et maladies et états associés
US9517224B2 (en) 2012-11-15 2016-12-13 The United States Of America As Represented By The Secretary, Department Of Health And Human Services Methods of treating patients infected with HIV and HTLV
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JP2018514526A (ja) * 2015-04-13 2018-06-07 アメリカ合衆国 癌および糖尿病の治療に有用なエポキシアズレン誘導体

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