WO2004106343A2 - Molecules et analogues de la famille agelastatine d'alkaloides antitumuraux et inhibiteurs de gsk-3? - Google Patents

Molecules et analogues de la famille agelastatine d'alkaloides antitumuraux et inhibiteurs de gsk-3? Download PDF

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WO2004106343A2
WO2004106343A2 PCT/GB2004/002306 GB2004002306W WO2004106343A2 WO 2004106343 A2 WO2004106343 A2 WO 2004106343A2 GB 2004002306 W GB2004002306 W GB 2004002306W WO 2004106343 A2 WO2004106343 A2 WO 2004106343A2
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process according
compound
following formula
catalyst
base
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WO2004106343A3 (fr
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Karl J. Hale
Mathias M. Domostoj
Edward Irving
Feodor Scheinmann
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Ufc Limited
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Priority claimed from GB0324639A external-priority patent/GB0324639D0/en
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Publication of WO2004106343A3 publication Critical patent/WO2004106343A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to alkaloids of the agelastatin family, in particular (-)-agelastatins A and B, and an enantiospecif ⁇ c process for their preparation.
  • the agelastatins are a structurally novel family of Oroidin alkaloids, obtained from marine sponges, that have powerful antitumour and insecticidal properties, both in vitro and in vivo (D'Ambrosio, M. et. al., J Chem. Soc. Chem. Comm. 1993, 135; Helv. Chim. Ada, 1994, 77, 1895; Helv. Chim. Acta. 1996, 79, 727).
  • ' (-)-Agelastatin A is also a potent and highly specific inhibitor of glycogen synthase kinase 3- ⁇ (GSK-3- ⁇ ) (Meijer, L. et al, Chem. & Biol, 2000, 7, 51).
  • GSK-3 ⁇ activity is associated with the hyperphosphorylation of tau, a microtubule-binding protein that forms neurofibrillary tangles when it becomes hyperphosphorylated (S. Lovestone et al, Curr. Biol, 1994, 4, 1077; A.J. Harwood, Cell, 2001, 105, 821). As these tangles are present in the brain tissues of patients with Alzheimer's disease (AD), and absent from the brains of normal subjects, it is widely believed that selective inhibitors of GSK-3 ⁇ activity could prove useful for treating neurodegenerative disorders such as AD.
  • AD Alzheimer's disease
  • GSK-3- ⁇ inhibitors could also function as novel insulin-mimetics, for insulin activates a cell- signalling pathway (the protein kinase B cascade) that inhibits GSK-3 ⁇ (Eldar- Finkelman, H. Trends Mol Med., 2002, 8, 126).
  • Inhibitors of upregulated GSK-3 - ⁇ activity might additionally act as neuroprotective agents preventing neuronal apoptosis after stroke (Martinez, A. et al, Medicinal Res. Rev., 2002, 22, 373).
  • molecules and analogues of the agelastatin family might have useful pharmacological properties, such as anticancer, anti-diabetic, anti-stroke, anti- inflammatory, immunosuppresant or anti-AD activity, and represent effective treatments for these diseases. They might also even serve as environmentally benign insecticides. New and readily modifiable synthetic pathways to these molecules are therefore of great interest and potential importance.
  • (-)-agelastatin A was reported to inhibit a human KB nasopharyngeal cancer cell line at the very low drug concentration of 0.075 ⁇ g/mL (this was its IC 50 ). It was also found to prolong the life expectancy of mice with L1210 murine leukaemia when repeatedly administered intraperitoneally at doses of 2.6 mg/kg, although no antitumour effects were noted when it was given intravenously.
  • the antitumour mechanism of (-)-agelastatin A has yet to be elucidated.
  • C— A and Z— C independently a single or a double bond
  • A C, N, O, S, or Se
  • Z C, N, O, S, or Se
  • R 1 , R 2 , R 3 , R 7 and R 8 are independently selected from H, C 1-10 alkyl, C J . IO cycloalkyl, aryl, substituted aryl, optionally substituted alkylaryl, halogen, haloalkyl, OR 9 , SR 9 , OH, NO 2 , CN, NH 2 , NHR 9 , N(R 9 ) 2 , NHOR 9 , NHCONHR 9 , NHCONR 9 2 , NR 9 COR 9 ,
  • R 9 H, C LIO alkyl, C LIO cycloalkyl, aryl, substituted aryl, optionally substituted alkylaryl;
  • C— A, X— Y, Y— Z, and Z— C independently a single or a double bond;
  • A, X, Y and Z independently selected from C, N, O, S, or Se;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are independently selected from H, C 1-10 alkyl, C 1-10 cycloalkyl, aryl, substituted aryl, optionally substituted alkylaryl, halogen, haloalkyl,
  • R 9 H, C LIO alkyl, C LIO cycloalkyl, aryl, substituted aryl, optionally substituted alkylaryl; n is any number of atoms that will produce a partially unsaturated or fully saturated 3 to 8 membered ring system containing 0 to 3 heteroatoms.
  • the compounds of the present invention may be obtained as a salt, preferably as a pharmaceutically acceptable salt of General Structure I and or General Structure II.
  • salts include, but are not limited to, those derived from organic acids such as acetic acid, malic acid, tartaric acid, citric acid, lactic acid, succinic acid, fumaric acid, maleic acid, oxalic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, methanesulfonic acid, benzenesulphonic acid and 7-toluenesulfonic acid, mineral acids such as hydrochloride and sulfuric acid and the like.
  • organic acids such as acetic acid, malic acid, tartaric acid, citric acid, lactic acid, succinic acid, fumaric acid, maleic acid, oxalic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, methanesulfonic acid, benzenesulphonic acid and 7-toluenesulfonic acid, mineral acids such as hydrochloride and sulfuric acid and the like.
  • suitable inorganic bases for the formation of salts of compounds of the present invention include the hydroxides, bicarbonates, carbonates and alkoxides of ammonia, lithium, sodium, potassium, calcium, aluminium, iron, magnesium, zinc, and the like. Salts can also be formed with suitable non-toxic organic bases such as arginine and lysine but may include mono-, di-, trihydroxyalkylamines, and mono-, di- and trialkylamines, and the like.
  • Salts may be prepared in a conventional manner by methods well-known in the art.
  • the compounds of this invention may also exist in solvated or hydrated or polymorphic forms.
  • a further aspect of the present invention provides a process for the enantiospecific synthesis of (-)-agelastatin A from D-glucosamine hydrochloride, wherein said process involves the enantiospecific synthesis of Boc-cyclopentene oxazolidinone (see compound 17 of scheme 1)
  • the process of the present invention provides an enantiospecific synthetic route to a very useful compound.
  • the synthetic route can be readily modified in order to prepare compounds analogous to (-)-agelastatin A.
  • the present invention includes the intermediates shown in Scheme 1 and methods for their synthesis.
  • the advanced intermediate III is prepared in enantiomerically pure form from D-glucosamine hydrochloride. Weinreb and co-workers previously converted racemic III into (+)-agelastatin A by a two step, one-pot, protocol that involved successive treatment of III with iodotrimethylsilane followed by methyl isocyanate and base (Stein, D., et. al, loc. ci ).
  • N- acyl derivatives of 2 show a marked preference (Buss, D.H.; Hough, L.; Richardson, A.C., J Chem. Soc, 1965, 2736; Guthrie, R.D.; Murphy, D. J. Chem. Soc. 1965, 3828; Hough, L.; Penglis, A.A.E.; Richardson, A.C. Carbohydrate Res., 1980, 83, 142; Gurjar, M.K.; Patil, V.J.; Yadav, J.S.; Rama Rao, AN. Carbohydrate Res.
  • a very smooth and highly regioselective aziridine ring-opening proceeds at 140°C with just 4 equiv of NaN 3 , the desired azide 4 being produced as the sole reaction product in 88% yield.
  • the azido group of 4 may be readily hydrogenolysed in the presence of a suitable catalyst such as Pearlman's catalyst to give the amine 5 which, without any further purification, is protected with a protecting group such SESC1 (Huang, J.; Widlanski, T.S. Tetrahedron Lett. 1992, 33, 2657.
  • Other protocols for SESC1 preparation include; Weinreb, S.M.; Demko, D.M.; Lessen, T.A.; Demers, J.P. Tetrahedron Lett. 1986, 27, 2099 and Weinreb, S.M.; Chase, C.E.; Wipf, P. Venkatraman, Org. Synth., 1997, 75, 161);
  • the O-benzylidene acetal of 6 is next detached by hydrolysis with, for example anhydrous methanolic HC1 to give 7.
  • iodide 10 is converted into iodide 10 by nucleophilic displacement with, for example, Nal in acetone at reflux.
  • Vasella reductive ring-opening (Bernet, B. et. al. Helv. Chim. Ada., 1976, 62, 1990; Bernet, B. et. al, Helv. Chim. Ada., 1976, 62, 2400) with zinc dust in aqueous THF.
  • Aldehyde 11 may then be methylenated by way of Kocienski's modification (Blakemore, P. R. et. al. Synlett, 1998, 26; Blakemore, P.R. et. al, J. Chem. Soc. Perkin Trans. 1, 1999, 955) of the Julia reaction (Baudin, J. B. Tetrahedron Lett. 1991, 32, 1175) with the anion derived from sulfone 12.
  • Hoveyda-Grubbs ruthenium alkylidene 14 (Kingsbury, J.S.; Harrity, J.P.A.; Bonitatebus, Jr., P.J.; Hoveyda, A.S. J. Am. Chem. Soc. 1999, 121, 791; S.B. Garber; Kingsbury, J.S.; Gray, B.L.; Hoveyda, A.M. J. Am. Chem. Soc 2000, 122, 8168) is by far the most effective and convenient catalyst currently available for effecting the ring-closing metathesis reaction of diene 13 to obtain cyclopentene 15.
  • catalyst 14 furnishes 15 in 41% overall yield for 3 steps; notwithstanding the presence of potentially troublesome urethane and sulfonamido NH groupings, which often deactivate the Grubb's RCM catalysts (for some leading reviews on RCM that discuss Ru alkylidenes in great detail, see: Grubbs, R.H.; Miller S.J.; Fu, G.C. Ace. Chem. Res., 1995, 28, 446; Grubbs, R.H.; Chang, S. Tetrahedron, 1998, 54, 4413; Furstner, A. Angew. Chem. Int. Ed. 2000, 39, 3012) of earlier vintage.
  • alkylidene 14 leads to higher yields of product 15 than its predecessor catalyst 27 (which is also effective for this RCM reaction); 14 is also much faster at converting 13 into 15.
  • the original Grubbs RCM catalyst 28 performs poorly in this ring-closure.
  • the O-desilylation of 15 may be effected by a fluoride ion source such as TBAF.
  • the TES group can be cleaved in 56-76% yield using an organic acid such as aqueous acetic acid in THF at room temperature (RT).
  • the latter may then be converted to the oxazolidinone 16 by K 2 CO 3 treatment in MeOH.
  • oxazolidinone 16 directly from 15 by heating 15 with a abse such as K 2 CO 3 in a solvent such as MeOH at reflux for 2 h.
  • Compound 16 may then be N-acylated using an acylating agent such as Boc 2 O with a catalyst such as DMAP in CH 2 C1 2 to provide (-)-17.
  • an acylating agent such as Boc 2 O
  • a catalyst such as DMAP in CH 2 C1 2
  • the use of Boc 2 O, DMAP and CH 2 C1 2 provides 17 in 62% yield.
  • Oxazolidinone 17 is an advanced intermediate in Weinreb's racemic total synthesis of agelastatin A. However, unlike Weinreb's route, the route described herein delivers (-)-17 in enantiomerically pure form for the very first time. The structure and absolute stereochemistry of (-)-17 was proven by single-crystal X-ray analysis (this was performed by Dr Arthur Tocher of the Chemistry Department, University College London).
  • the SES group of 19 can be cleaved using TBAF, as reported by Weinreb, such cleavage was found to be problematical, typically proceeding in only a 33% yield compared to a reported yield of 66%. Therefore, alternative procedures have been developed.
  • the SES group of 19 may be cleaved using an fluoride ion source such as CsF in DMF at RT for 19 hours, prior to heating it at 50°C for 1 hour.
  • the use of CsF furnishes the desired product (-)-20 in a yield of 46-68%.
  • the selective hydrolysis of the oxazolidinone in 20 may be carried out in accordance with Weinreb's procedure which employs LiOH in THF.
  • An alternative procedure which yields similar results employs a base such as Cs 2 CO 3 in a solvent such as MeOH.
  • the selective hydrolysis provides a 7:3 mixture of products 22:21. Due to the difficulties of separating 22 from 21 by SiO 2 flash chromatography a chromatographed (but not separated) mixture of 22 and 21 is oxidized using, for example, TPAP and NMO to obtain a mixture of 23 and 21. Weinreb carried this oxidation step using the CrO /Py protocol well known to those skilled in the art.
  • the TPAP oxidation is much easier to work-up than the CrO 3 /Py protocol, and uses only catalytic quantities of the transition metal oxidant, which is preferable for large scale industrial work.
  • TLC analysis of the crude reaction mixture invariably indicates the presence of three main reaction components: 24, (-)-25, and (-)-21.
  • Compounds 24, (-)-25, and (-)-21 are now readily separated by SiO 2 flash chromatography; the desired product (-)-25 is generally isolated in 18% overall yield for the three steps from (-)-20.
  • Weinreb has previously converted (+)-26 into (+)-agelastatin A by a two-step, one-pot, operation. Therefore, it will now be possible to obtain (-)-agelastatin and its congeners from (-)-26.
  • a new, alternative, synthetic pathway has been devised to provide (-)-agelastatins A and B from a key intermediate in the above formal route, namely, the oxazolidinone (-)-16.
  • the new route now provides (-)-agelastatins A and B as a 4: 1 mixture enriched in the former molecule.
  • a further aspect of the present invention provides a process for enantiospecific synthesis of (-)-agelastatins A and B, characterised in that the process comprises a step of cleaving the SES group from a pyrrole carboxamide of the following formula:
  • the organotin hydride may comprise Bu SnH.
  • the free radical initiator may comprise AIBN.
  • the solvent may be any suitable organic solvent, such as benzene or toluene. Preferably, the reaction is carried out at reflux.
  • the pyrrole carboxamide 29 may be prepared from an oxazolidinone of the following formula:
  • reaction by N-acylation on its sulfonamido nitrogen with the pyrrole acid chloride 18.
  • the reaction may be carried out using DMAP and Et 3 ⁇ in a non-protic organic solvent, such as THF.
  • the oxazolidinone 28 may be prepared by regioselective N-acylation of the oxazolidinone 16 with an acid chloride of the following formula:
  • This may be achieved, for example, using an inorganic base, such as LiOH, in a polar solvent, such as THF water.
  • a polar solvent such as THF water.
  • This step is followed by oxidation of the allylic alcohol 31 to provide a cyclopentenone of the following formula:
  • This oxidation is preferably effected with a mild oxidative agent such as pyridinium dichromate (PDC) in DMF; certain other oxidants, such as tetra- «-propylammonium perruthenate, generally cause significant product decomposition and so are not recommended.
  • a mild oxidative agent such as pyridinium dichromate (PDC) in DMF
  • PDC pyridinium dichromate
  • certain other oxidants such as tetra- «-propylammonium perruthenate, generally cause significant product decomposition and so are not recommended.
  • the cyclopentenone 32 is then subjected to Michael cyclisation.
  • the direct Michael-cyclisation of 32 mediated by Cs 2 CO 3 in MeOH, is ineffective at bringing about the desired conjugate addition of the pyrrole nitrogen to the enone system.
  • a multiple enolisation/reprotonation process takes place exclusively, with the result that an olefm transposition occurs to give the more substituted and stable cyclopentenone IV:
  • the cyclisation may be brought about by adding an excess of a mild organic base, such as triethylamine, to the crude reaction mixture, and stirring the reactants for a prolonged period of time; this overcomes the cyclopentenone isomerisation problem which is only an issue when strong bases are used in the ⁇ H(CO) ⁇ (Me)Bn substituted systems.
  • a mild organic base such as triethylamine
  • a further step in our synthesis of (-)-agelastatins A and B is the bromination of (-)-37, for example with NBS in a solvent such as THF/MeOH following the published procedure of Feldman and Saunders (Feldman, K.S., loc. cit.).
  • a 4:1 mixture of optically pure (-)- agelastatins A and B in ca. 50% yield has been observed.
  • the process of this aspect of the present invention provides a very useful pair of compounds, (-)-agelastatins A and B, and can be readily modified to prepare analogue structures.
  • the present invention includes all of the intermediates shown in Scheme 2 and methods for their synthesis in enantiomerically pure form.
  • the new process facilitates the production of a compound of general structure I:
  • R 1 , R 2 , R 3 , R 7 and R 8 are independently selected from H, C 1-10 alkyl, C O cycloalkyl, aryl, substituted aryl, optionally substituted alkylaryl, halogen, haloalkyl, OR 9 , OH, NO 2 , CN, NH 2 , NHR 9 , N(R 9 ) 2 , NHOR 9 , NHCONHR 9 , NHCONR 9 2 , NR 9 COR 9 , NHCO 2 9 , CO 2 R 9 , CO 2 H, COR 9 , CONHR 9 , CONR 9 2 , S(O) 2 R 9 , S(O)R 9 , SONH 2 , SO 2 NHR 9 , NHS(O) 2 R 9 groups, or an optionally substituted heterocyclic group;
  • R 9 H, C MO alkyl, C 1-10 cycloalkyl, aryl, substituted aryl, optionally substituted alkylaryl;
  • the new process also facilitates in particular the production of a compound of general structure II:
  • A O orN; and X, Y, and Z are independently selected from C, N, or O; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are independently selected from H, C 1-10 alkyl, C 1-10 cycloalkyl, aryl, substituted aryl, optionally substituted alkylaryl, halogen, haloalkyl, OR 9 , SR 9 , OH, NO 2 , CN, NH 2 , NHR 9 , N(R 9 ) 2 , NHOR 9 , NHCONHR 9 , NHCONR 9 2 , NR 9 COR 9 , NHCO 2 9 , CO 2 R 9 , CO 2 H, COR 9 , CONHR 9 , CONR 9 2 , S(O) 2 R 9 , S(O)R 9 , SONH 2 , SO 2 NHR 9 , NHS(O) 2 R 9 groups, or an optionally substituted hetero
  • At least one compound of general structure I and/or general structure II as hereinbefore defined for use as a medicament there is provided at least one compound of general structure I and/or general structure II as hereinbefore defined for use as a medicament.
  • a therapeutically effective non-toxic amount of a compound of general structure I and/or general structure II as hereinbefore defined may be administered in any suitable manner, including orally, parenterally (including subcutaneously, intramuscularly and intravenously), or topically.
  • the administration will generally be carried out repetitively at intervals, for example once or several times a day.
  • the amount of the compound of general structure I and/or general structure II that is required in order to be effective as an anti-diabetes, anticancer, anti-inflammatory agent or anti-AD agent for treating human or animal subjects will of course vary and is ultimately at the discretion of the medical or veterinary practitioner treating the human or animal in each particular case.
  • the factors to be considered by such a practitioner, e.g. a physician, include the route of administration and pharmaceutical formulation; the subject's body weight, surface area, age and general condition; and the chemical form of the compound to be administered.
  • the total daily dose may be given as a single dose, multiple doses, e.g. two to six times per day, or by intravenous infusion for any selected duration.
  • the compound of general structure I and/or general structure II may be presented, for example, in the form of a tablet, capsule, liquid (e.g. syrup) or injection.
  • a pharmaceutical composition containing a compound of general structure I and/or general structure II as hereinbefore defined, or a pharmaceutically acceptable salt thereof, as an active ingredient.
  • compositions for medical use will be formulated in accordance with any of the methods well known in the art of pharmacy for administration in any convenient manner.
  • the compounds of the invention will usually be admixed with at least one other ingredient providing a compatible pharmaceutically acceptable additive, carrier, diluent or excipient, and may be presented in unit dosage form.
  • the carrier(s) must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the possible formulations include those suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration or for administration to the lung or another absorptive site such as the nasal passages.
  • All methods of formulation in making up such pharmaceutical compositions will generally include the step of bringing the compound of general structure I and/or general structure II into association with a carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing the compound of general structure I and/or general structure II into association with a liquid carrier or with a finely divided solid carrier or with both and then, if necessary, shaping the product into desired formulations.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the compound of general structure I and/or general structure II; as a powder or granules; or a suspension in an aqueous liquid or non-aqueous liquid such as a syrup, an elixir, an emulsion or a draught.
  • the compound of general structure I and or general structure II may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the compound of general structure I and/or general structure II in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent.
  • Moulded tablets may be made by moulding, in a suitable machine, a mixture of the powdered compound of general structure I and/or general structure II with any suitable carrier.
  • a syrup may be made by adding the compound of general structure I and/or general structure II to a concentrated, aqueous solution of a sugar, for example sucrose, to which may be added any desired accessory ingredient.
  • a sugar for example sucrose
  • Such accessory ingredient(s) may include flavourings, an agent to retard crystallisation of the sugar or an agent to increase the solubility of any other ingredient, such as a polyhydric alcohol, for example glycerol or sorbitol.
  • Formulations for rectal administration may be presented as a suppository with a usual carrier such as cocoa butter.
  • Formulations suitable for parental administration conveniently comprise a sterile aqueous preparation of the compound of general structure I and/or general structure II which is preferably isotonic with the blood of the recipient.
  • formulations of this invention may include one or more accessory ingredients, for example a diluent, buffer, flavouring agent, binder, surface active agent, thickener, lubricant and/or a preservative (including an antioxidant) or other pharmaceutically inert excipient.
  • accessory ingredients for example a diluent, buffer, flavouring agent, binder, surface active agent, thickener, lubricant and/or a preservative (including an antioxidant) or other pharmaceutically inert excipient.
  • the compounds of this invention may also be made up for administration in liposomal formulations which can be prepared by methods well-known in the art.
  • a further aspect of the present invention provides the use of at least one compound of general structure I and/or general structure II as hereinbefore defined, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
  • a further aspect of the present invention provides the use of at least one compound of general structure I and/or general structure II as hereinbefore defined, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of diabetes.
  • a further aspect of the present invention provides the use of at least one compound of general structure I and/or general structure II as hereinbefore defined, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of Alzheimer's disease.
  • a further aspect of the present invention provides the use of at least one compound of general structure I and/or general structure II as hereinbefore defined, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of inflammation.
  • a further aspect of the present invention provides at least one compound of general structure I and or general structure II in the form of a pro-drug derivative, or pharmaceutically acceptable salt thereof, for use as a medicament.
  • a pharmaceutical composition comprising, as an active ingredient, at least one compound of general structure I and/or general structure II, or a pharmaceutically acceptable salt thereof, wherein the said composition is in the form of a pro-drug derivative.
  • the said pro-drug includes ester, amide or glycoside derivatives of the compounds of General Structures I and II. Methods for the preparation of such pro-drugs derivatives are well known to those skilled in the art
  • pro-drug molecules are capable of being converted to any of the compounds of the present invention, or indeed their pharmaceutically acceptable salts, under physiological conditions or through hydrolysis. This may lead to a more potent treatment as the conversion generally occurs in the body at or near to the treatment site. Furthermore, pro-drugs can be more stable and therefore have longer shelf lives and are easier to transport than their active counterparts.
  • the pro-drug derivative as hereinbefore described may be used in the manufacture of a treatment for cancer, diabetes, Alzheimer's Disease or inflammation.
  • a method of treatment of cancer which comprises administering to a human or an animal in need of such treatment a therapeutically effective amount of a compound of general structure I and or II as hereinbefore defined or a pro-drug or pharmaceutically acceptable salt thereof.
  • a method of treatment of diabetes which comprises administering to a human or an animal in need of such treatment a therapeutically effective amount of a compound of general structure I and or II as hereinbefore defined or a pro-drug or pharmaceutically acceptable salt thereof.
  • a method of treatment of Alzheimer's disease which comprises administering to a human or an animal in need of such treatment a therapeutically effective amount of a compound of general structure I and or II as hereinbefore defined or a pro-drug or pharmaceutically acceptable salt thereof.
  • a method of treatment of inflammation which comprises administering to a human or an animal in need of such treatment a therapeutically effective amount of a compound of general structure I and or II as hereinbefore defined or a pro-drug or pharmaceutically acceptable salt thereof.
  • Agelastatin A was dosed at 2.5 mg/kg to a test group and compared with a control group which was dosed with the vehicle compound alone at 20 ml/kg. The efficacy was evaluated by taking measurements of the actual tumour volumes. The results can be seen below:
  • the aqueous layer was extracted with CH 2 C1 2 (2 x 15 mL), and the combined organic layers washed with 1M aq. HCl (10 mL), sat. aq. NaHCO 3 (10 mL), dried (MgSO 4 ), and filtered.
  • the solvent was removed in vacuo and the crude residue recrystallised from EtO Ac/petrol to provide 17 (807 mg, 50%) as a white crystalline solid.
  • the mother liquors were concentrated in vacuo, and the residue purified by SiO 2 flash chromatography with 3:2 PetrohEtOAc to provide a further quantity of 17 (210 mg, 62% overall).
  • Protocol A To a solution of the sulfonamide 19 (348 mg, 0.675 mmol) in dry DMF (3.5 mL) was added CsF (103 mg, 0.675 mmol) at RT and the mixture stirred at RT for 19 h before being heated at 50 °C for 1 h. After cooling to RT, H 2 O (50 mL) was added and the aqueous solution was extracted with EtOAc (6 x 15 mL). The combined organic layers were washed with H 2 O (10 mL) and brine (10 mL), dried (MgSO 4 ), and filtered.
  • N-Boc- ⁇ -amino-ketone (-)-25 110 mg, 0.292 mmol
  • N-bromosuccinimide 62 mg, 351 mmol
  • the reactants were stirred at 0 °C for 1 h and then at RT for a further 5 h. Sat. aq. ⁇ aHC0 3 (20 mL) and sat. aq. Na 2 S 2 O 3 (5 ml) were added to the mixture, and the product 26 extracted with EtOAc (3 x 50 mL).
  • (+)-26 has previously been converted into racemic agelastatin A by Weinreb et al. Enantiomerically pure (-)-26 will thus yield (-)-agelastatin A, if subjected to the same protocol.

Abstract

L'invention concerne un composé de structure générale (I) ou un sel pharmaceutiquement tolérable de celui-ci. Dans la structure générale (I) C---A et Z---C représentent indépendamment une liaison simple ou double; A représente C, N, O, S ou Se; Z représente C, N, 0, S ou Se; R1, R2, R3, R7 et R8 sont indépendamment sélectionnés parmi H, les groupes CI-10 alkyle, Cl-10 cycloalkyle, aryle, aryle substitué, alkylaryle éventuellement substitué, halogène, haloalkyle, OR9, SR9, OH, N02 CN, NH2, NHR9, N(R9)2, NHOR9, NHCONHR9, NHCONR92, NR9COR9, NHC02R9, C02R9, C02H, COR9, CONHR9, CON(R9)2, S(O)2R9, S(O)R9, SONH2 SO2NHR9, NHS(O)2R9, et Si(R9)3 ou représentent un groupe hétérocyclique éventuellement substitué; et R9 = H, Cl-10 alkyle, Cl-10 cycloalkyle, aryle, aryle substitué, alkylaryle éventuellement substitué.
PCT/GB2004/002306 2003-05-30 2004-06-01 Molecules et analogues de la famille agelastatine d'alkaloides antitumuraux et inhibiteurs de gsk-3? WO2004106343A2 (fr)

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GB0312429A GB0312429D0 (en) 2003-05-30 2003-05-30 Molecules and analogues of the agelastatin family of antitumour and GSK-3 -inhibiting alkaloids
GB0312429.4 2003-05-30
GB0324639A GB0324639D0 (en) 2003-10-22 2003-10-22 Molecules and analogues of the agelastatin family of antitumour and GSK-3 -inhibiting alkaloids
GB0324639.4 2003-10-22

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008017381A1 (fr) 2006-08-08 2008-02-14 Sanofi-Aventis Imidazolidin-2,4-dione arylaminoaryl-alkyl-substituée, son procédé de fabrication, médicament contenant ce composé et son utilisation
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WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
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WO2012120057A1 (fr) 2011-03-08 2012-09-13 Sanofi Nouveaux dérivés phényl-oxathiazine substitués, procédé pour leur préparation, agent pharmaceutique contenant ces composés et leur utilisation
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WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
CN102643175B (zh) * 2005-07-04 2014-12-10 赞南科技(上海)有限公司 钌络合物配体、钌络合物、固载钌络合物催化剂及其制备方法和用途
US9962383B2 (en) 2013-09-19 2018-05-08 Massachusetts Institute Of Technology Compounds, compositions and methods of agelastatin alkaloids
WO2018209239A1 (fr) * 2017-05-11 2018-11-15 Massachusetts Institute Of Technology Dérivés d'agélastatine puissants en tant que modulateurs de l'invasion et de la métastase du cancer
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US11535634B2 (en) 2019-06-05 2022-12-27 Massachusetts Institute Of Technology Compounds, conjugates, and compositions of epipolythiodiketopiperazines and polythiodiketopiperazines and uses thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FELDMAN, KEN S. ET AL: "Alkynyliodonium Salts in Organic Synthesis. Development of a Unified Strategy for the Syntheses of (-)-Agelastatin A and (-)-Agelastatin B" JOURNAL OF ORGANIC CHEMISTRY, vol. 67, no. 20, 2002, pages 7096-7109, XP002299742 *
STIEN, DIDIER ET AL: "Total Synthesis of the Antitumor Marine Sponge Alkaloid Agelastatin A" JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 121, no. 41, 1999, pages 9574-9579, XP002299741 cited in the application *

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