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WO1992016486A1 - Diphenylethylenes substitues et leurs analogues ou derives - Google Patents

Diphenylethylenes substitues et leurs analogues ou derives Download PDF

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Publication number
WO1992016486A1
WO1992016486A1 PCT/GB1992/000498 GB9200498W WO9216486A1 WO 1992016486 A1 WO1992016486 A1 WO 1992016486A1 GB 9200498 W GB9200498 W GB 9200498W WO 9216486 A1 WO9216486 A1 WO 9216486A1
Authority
WO
WIPO (PCT)
Prior art keywords
combretastatin
phosphate
compound
benzaldehyde
ethene
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.)
Ceased
Application number
PCT/GB1992/000498
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English (en)
Inventor
Daniel Lee Rathbone
John Alfred Slack
Roger John Griffin
Charmaine Paulina Quarterman
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ASTON MOLECULES Ltd
Original Assignee
ASTON MOLECULES Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by ASTON MOLECULES Ltd filed Critical ASTON MOLECULES Ltd
Publication of WO1992016486A1 publication Critical patent/WO1992016486A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/54—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • This invention relates to substituted diphenyl- ethylenes of the kind exemplified by the compound known as Combretastatin A4 (cis-l-(3-Hydroxy-4-methoxyphenyl)-
  • Combretastatin A4 in particular is known from the work of G.R. Pettit et al. (see, for example, Pettit, G.R., et al. Experientia, 1989, 4_5, 209-211), and has been shown to be active in vitro as an inhibitor of tubulin polymerisation and, additionally, to inhibit the growth of murine lymphocytic leukemia. It is accordingly of interest as a promising therapeutic agent for use in chemotherapy, especially as an anti-neoplastic or anti- cancer agent, but unfortunately it has been found to have limited solubility in pharmaceutically acceptable solvents and this characteristic has delayed its entry into Phase I clinical trials. Also, it has not been easy to synthesise efficiently.
  • the present invention has developed from efforts to devise an improved process for synthesizing Combretastatin A4 and from efforts to produce analogues or derivatives having greater aqueous solubility, more suitable for use in pharmaceutical formulations, and capable of acting as pro-drugs which can be biologically degraded or broken down to release the active Combretastatin A4 component within the body after being administered to a patient in need of treatment.
  • pro-drugs generally exhibit greater stability to oxidative decomposition than the parent drug.
  • the invention provides a process for preparing a substituted diphenyl- ethylene compound having the general structure
  • R- ⁇ , 2 3 and R4 are alkoxy groups
  • Y is hydrogen, a phosphate or phosphate derivative, an amino acid carbamate derivative, or a derivative of a carbohydrate or polyhydroxylated compound, the process being characterised in that it is a convergent process that includes the step of reacting, in a Wittig coupling reaction, an ylide triphenyl phosphonium salt of a trialkoxy benzyl halide with a benzaldehyde compound:
  • X comprises a silyl group or phosphate ester group.
  • the alkoxy groups generally each contain 1-6 carbon atoms, and are most preferably methoxy or ethoxy.
  • the process of the invention also provides a number of novel intermediate compounds.
  • the invention further provides novel analogues or derivatives of Combretastatin A4 ( cis isomer of Compound I wherein Y is hydrogen) which have enhanced aqueous solubility and photostability and which are especially suitable for use as pro-drugs in pharmaceutical formulations for clinical use.
  • the invention also includes pharmaceutical formulations comprising or containing such novel analogues or derivatives made up for administration in any suitable manner, for example parentally (including intravenously, intramuscularly and subcutaneously) or orally.
  • Such formulations containing or incorporating therapeutically effective non-toxic amounts, conveniently in unit dosage form, of the active drug compound, together possibly with at least one other ingredient providing a compatible pharmaceutically acceptable additive, diluent or excipient, may be prepared by any of the methods well known in the art of pharmacy.
  • novel analogues of Combretastatin A4 are phosphate derivatives and salts thereof which have enhanced aqueous solubility and which are susceptible to enzymic dephosphorylation so that they can act as pro-drugs of Combretastatin A4.
  • novel analogues that may also serve as satisfactory biodegradable pro-drugs comprise amino-acid carbamate derivatives, e.g. glycine carbamate derivatives, and carbohydrate or polyhydroxylated derivatives.
  • Combretastatin A4 and Combretastatin A4 analogues particularly Combretastatin A4 phosphate (including salts thereof) and Combretastatin A4 glycine carbamate derivatives.
  • Combretastatin A4 phosphate has been shown to be stable in aqueous solution and to degrade in vitro to Combretastatin A4 when incubated with either acid phosphatase or alkaline phosphatase.
  • Combretastatin A4 phosphate can be determined by HPLC using the following chromatographic conditions:
  • Combretastatin A4 has a retention time of approximately 11 minutes.
  • Combretastatin A4 phosphate has been determined by visualisation. By progressively adding small known amounts of the material to 2ml water the solubility of this salt was found to be approximately 2.8mg/ml.
  • Aqueous Stability A solution of Combretastatin A4 Phosphate diammonium salt (approximately 0.14mg/ml) was protected from light and stored at room temperature. Aliquots were taken over a 6 hour period and analysed by HPLC in order to determine stability. The A4 phosphate was shown to be stable over this period.
  • Combretastatin A4 phosphate was incubated at 37°C in lO M tris buffer, pH 8. In the presence of calf intestinal phosphatase the A4 phosphate was dephosphorylated to produce Combretastatin A4. In contrast, Combretastatin A4 phosphate was stable in a control incubation containing no enzyme.
  • 3,4,5-Trimethoxybenzyl alcohol was brominated to give 3,4,5-trimethoxybenzyl bromide in 86% yield. This was converted immediately into the corresponding triphenylphosphonium salt in 84% yield.
  • 3-Hydroxy-4-methoxybenzaldehyde was silyl- ated in 92% yield to give the protected form 4- methoxy-3-(thexyldimethysilyloxy)benzaldehyde. This was coupled in a Wittig coupling reaction to the ylide form of the phosphonium salt from above to give a 1/1 mixture of the silylated Combretastatin A4 and its trans isomer.
  • the key step is the Wittig coupling of the ylide from 3,4,5-trimethoxybenzylphosphonium bromide and 4- methoxy-3-(thexyldimethylsilyloxy)benzaldehyde.
  • the latter compound, the product from the Wittig coupling step, the three Combretastatin A4 phosphate derivatives and the glycine carbamate derivative detailed above are all novel compounds so far unreported in the literature.
  • Trimethylchlorosilane (28.0ml, 0.221mol) was added to a vigorously stirred suspension of lithium bromide (15.6g, 0.180mol) in dry acetonitrile (200ml) under an atmosphere of argon. To this was added 3,4,5- trimethoxybenzyl alcohol (17.82g, 0.090mol) dissolved in dry acetonitrile (15ml). This resulted in a homogeneous solution which was set aside at room temperature for 18 hours by which time a white precipitate had formed. Ethyl acetate (100ml) was added and the solution was washed successively with water (2x150ml), saturated sodium hydrogen carbonate solution (2x50ml) and water (50ml).
  • MCPBA 50% MCPBA (2.30g, nominally ⁇ . ⁇ mmol) was dissolved in dichloromethane (20ml) and dried over magnesium sulphate.
  • the mixture was filtered and used as such in the reaction described below.
  • the mixture was stirred at -70°C for 15 minutes and then warmed to room temperature over 10 minutes before being quenched with a 10% aqueous solution of sodium sulphite (25ml).
  • the mixture was stirred for 10 minutes and then extracted with dichloromethane (3x30ml).
  • the dichloromethane portions were combined and washed with saturated aqueous sodium hydrogen carbonate (20ml).
  • the aqueous layer was back-extracted with dichloromethane (30ml).
  • the dichloromethane portions were combined, dried over magnesium sulphate and evaporated under reduced pressure.
  • the residue was chromatographed on silica, eluting with acetone-petrol (bp 60-80 ⁇ C) 3/7.
  • the resin was washed with water (40ml). The water portions were combined and freeze dried to give the crude potassium salt as a white fluffy solid (0.53g).
  • the crude product was dissolved in water (35ml) and treated with acetone (500ml).
  • a white crystalline solid separated out which was collected by filtration and dried in vacuo to give combretastatin A4 phosphate potassium salt as a white crystalline solid (0.30g, 0.63mmol, 55% yield), mp 177.4-179.1°C (decomp. corrected).
  • 3-Hydroxy-4-methoxybenzyl-n-butylimine (5.Og, 32.9mmol), ji-butylimine (6ml, 60.3mmol) and p-toluene- sulphonic acid mono-hydrate (O.lg, O.Smmol) were heated together at reflux in toluene (150ml) in conjunction with a soxhlet apparatus charged with magnesium sulphate for 24 hours. The solvent and excess n-butylimine were removed by evaporation to give crude 3-Hydroxy-4- methoxybenzyl-n-butylimine as a brown oil (6.1g, 29.5mmol), 90%). This was used in the next stage without purification.
  • n-Butyllithium (2.5M in hexanes, 0.6ml, 1.5mmol) was added to a stirred ice-cold suspension of 3,4,5- ri ethoxybenzyl triphenylphosphonium bromide (0.76g, I.46mmol) in THF (30ml) under argon. The mixture was stirred at room temperature for 1 hour during which time a deep-red coloured homogeneous solution was formed. 4- Methoxy-3-(0-phosphate)benzaldehyde bis t-butyl ester (0.50g, 1.45mmol) dissolved in THF (5ml) was added and the solution was stirred in the dark for 1 hour.
  • reaction mixture was poured onto water (20ml) and extracted with ethyl acetate (50ml). The organic layer was dried over magnesium sulphate and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica, eluting with ethyl acetate- petrol (60-80) 1/1.
  • Trifluoromethanesulphonic acid (8 drops) was added to an ice-cold solution of the stilbene isomer mixture (0.14g, 0.28mmol) in dichloromethane (10ml) in the dark. After 1 hour the solvent was evaporated under reduced pressure. Ethanol (10ml) was added and then evaporated under reduced pressure. This was repeated twice. The residue was dissolved in ethanol (5ml) . Concentracted ammonia aqueous solution ("0.88", 6 drops) was added and a white precipitate Combretastatin A4 phosphate ammonium salt formed. This was collected by filtration, dissolved in water (10ml) and stirred with Dowex (Regd.
  • novel analogues or derivatives of Combretastatin A4 provided by the present invention, especially although not exclusively such analogues or derivatives which are biodegradable in vivo to Combretastatin A4 and which are soluble in water, for example Combretastatin A4 phosphate or salts thereof, amino-acid carbamate derivatives, carbohydrate derivatives and polyhydroxylated derivatives, are particularly useful as pro-drugs that may be made up into pharmaceutical formulations for administration in the therapeutic treatment for example of mammals suffering from neoplastic diseases or cancer.
  • a predetermined therapeutically effective non-toxic amount of the particular analogue or derivative concerned may be dissolved in phosphate buffered saline and the preparations may be presented in unit dosage form and contained in sealed ampoules ready for use.
  • concentrations not greater than 2mg/ml will be preferred, but the amount and dosage routine required for optimum effectiveness will of course vary and is ultimately at the discretion of the medical or veterinary practioner treating the mammal in each particular case.
  • the invention provides a number of different aspects and, in general, it embraces all novel and inventive features and aspects, including novel compounds, herein disclosed either explicitly or implicitly and either singly or in combination with one another. Moreover, the scope of the invention is not to be construed as being limited by the illustrative examples or by the terms and expressions used herein merely in a descriptive or explanatory sense.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Des diphényléthylènes substitués tels que le composé connu sous le nom de Combretastatine A4 (cis-1-3-hydroxy-4-méthoxyphényl-2,3,4,5-triméthoxyphényléthène, ainsi que leurs dérivés ou analogues, sont synthétisés dans un procédé convergent dans lequel la forme ylide d'un sel de phosphonium de triphényle d'un halogénure de trialkoxybenzyle est soumise à une réaction de copulation de Wittig avec un composé de benzaldéhyde possédant un groupe protégé hydroxyle ou O-phosphate dans la position 3 et un groupe alkoxy dans la position 4. Les analogues et dérivés de Combretastatine A4 présentant des caractéristiques améliorées ou amplifiées de photostabilité et de solubilité aqueuse sont décrits par l'invention comme pouvant s'utiliser en tant que précurseurs de médicaments biodégradables dans des formulations pharmaceutiques destinées à des applications cliniques.
PCT/GB1992/000498 1991-03-22 1992-03-19 Diphenylethylenes substitues et leurs analogues ou derives Ceased WO1992016486A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9106177.0 1991-03-22
GB919106177A GB9106177D0 (en) 1991-03-22 1991-03-22 Substituted diphenylethylenes and analogues or derivatives thereof

Publications (1)

Publication Number Publication Date
WO1992016486A1 true WO1992016486A1 (fr) 1992-10-01

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GB (1) GB9106177D0 (fr)
WO (1) WO1992016486A1 (fr)

Cited By (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994005682A1 (fr) * 1992-08-31 1994-03-17 Francesca Pelizzoni Derives de combretastatine a activite antitumorale et leur procede de preparation
EP0731085A1 (fr) 1995-03-07 1996-09-11 Ajinomoto Co., Inc. Dérivés de stylbène et compositions pharmaceutiques les contenant
US5561122A (en) * 1994-12-22 1996-10-01 Arizona Board Of Regents Acting On Behalf Of Arizona State University Combretastatin A-4 prodrug
US5569786A (en) * 1987-01-06 1996-10-29 Arizona Board Of Regents Acting On Behalf Of Arizona State University Isolation, structural elucidation and synthesis of novel antineoplastic substances denominated "combretastatins"
WO2000048590A1 (fr) * 1999-02-16 2000-08-24 Angiogene Pharmaceuticals Ltd. Composes de stilbene substitue ayant une activite de degradation vasculaire
WO2001012579A3 (fr) * 1999-08-12 2001-10-11 Angiogene Pharm Ltd Nouveaux stilbenes a activite de degradation vasculaire
WO2001081355A1 (fr) * 2000-04-27 2001-11-01 Arizona Board Of Regents, A Body Corporate Of The State Of Arizona,Acting For And On Behalf Of Arizona State University Promedicaments a base de combretastatine a-1 phosphate et de combretastatine b-1 phosphate
WO2001042231A3 (fr) * 1999-12-06 2001-11-01 Welichem Biotech Inc Traitement anti-inflammatoire et psoriasique et inhibition de la proteine kinase par des hydroxylstilbenes et de nouveaux derives de stilbene ou analogues
WO2002022626A1 (fr) * 2000-09-14 2002-03-21 Bristol-Myers Squibb Company Sels mono- et di-amine organique, sels mono- et di-acide amine et sels mono- et di-ester d'acide amine de promedicaments a base de combretastatine a-4 phosphate
EP1045853A4 (fr) * 1998-01-09 2002-04-17 Univ Arizona State Synthese de promedicaments a base de combrestatine a-4 et de leurs trans-isomeres
WO2002050007A3 (fr) * 2000-12-21 2002-10-17 Cancer Res Ventures Ltd Stilbenes substituees et leurs reactions
EP1068870A4 (fr) * 1998-04-03 2003-02-12 Ajinomoto Kk Agents antitumoraux
US6743937B2 (en) 2000-07-17 2004-06-01 Oxigene, Inc. Efficient method of synthesizing combretastatin A-4 prodrugs
EP1559718A1 (fr) * 2000-09-14 2005-08-03 Bristol-Myers Squibb Company Sels de phosphates de combrétastatine A-4 avec des composés contenant de l'azote comme prodrogués
EP1438281A4 (fr) * 2001-10-26 2006-04-26 Oxigene Inc Derives de stilbene fonctionnalises, utiles comme agents de ciblage vasculaire ameliores
US7105501B2 (en) * 2000-08-15 2006-09-12 Angiogene Pharmaceuticals Ltd. Compositions with vascular damaging activity
CN1312161C (zh) * 2005-04-30 2007-04-25 中国科学院广州化学研究所 4，3’，4’，5’－四甲氧基联苄－3－o－磷酸酯盐及其组合物、制备方法和应用
US7321050B2 (en) 1999-12-06 2008-01-22 Welichem Biotech Inc. Anti-inflammatory and psoriasis treatment and protein kinase inhibition by hydroxy stilbenes and novel stilbene derivatives and analogues
US7524832B2 (en) 2000-09-14 2009-04-28 Bristol-Myers Squibb Co. Combretastatin A-4 phosphate prodrug mono-and di-organic amine salts, mono-and di-amino acid salts and mono-and di-amino acid ester salts
WO2009067706A1 (fr) 2007-11-21 2009-05-28 Oxigene, Inc. Procédé pour traiter des néoplasmes hématopoïétiques
CN1907989B (zh) * 2005-08-02 2011-08-17 浙江天皇药业有限公司 毛兰素盐及其制备方法和包含其的药物组合物
EP2289521A3 (fr) * 1999-02-18 2011-10-05 Arizona Board Of Regents Compositions et procédé d'utilisation pour le ciblage de la destruction vasculaire
US8062880B2 (en) 2007-04-13 2011-11-22 Freeman Energy Corporation Biomass cultivation system and corresponding method of operation
US8198302B2 (en) 2003-02-28 2012-06-12 Oxigene, Inc. Compositions and methods with enhanced therapeutic activity
US10201623B2 (en) 2013-03-15 2019-02-12 Memorial Sloan Kettering Cancer Center HSP90-targeted cardiac imaging and therapy
WO2019189554A1 (fr) 2018-03-30 2019-10-03 国立大学法人京都大学 Promoteur de maturation de cardiomyocytes
US10640508B2 (en) 2017-10-13 2020-05-05 Massachusetts Institute Of Technology Diazene directed modular synthesis of compounds with quaternary carbon centers
US10647649B2 (en) 2017-11-10 2020-05-12 Dermavant Sciences GmbH Process for preparing tapinarof
WO2020247054A1 (fr) 2019-06-05 2020-12-10 Massachusetts Institute Of Technology Composés, conjugués et compositions d'épipolythiodicétopipérazines et de polythiodicétopipérazines et leurs utilisations
US10918627B2 (en) 2016-05-11 2021-02-16 Massachusetts Institute Of Technology Convergent and enantioselective total synthesis of Communesin analogs
US10918735B2 (en) 2012-12-04 2021-02-16 Massachusetts Institute Of Technology Substituted pyrazino[1′,2′:1,5]pyrrolo[2,3-b]indole-1,4-diones for cancer treatment
US11419934B2 (en) 2015-08-18 2022-08-23 Oncotelic Therapeutics, Inc. Use of VDAS to enhance immunomodulating therapies against tumors
US11932650B2 (en) 2017-05-11 2024-03-19 Massachusetts Institute Of Technology Potent agelastatin derivatives as modulators for cancer invasion and metastasis
US12030888B2 (en) 2021-02-24 2024-07-09 Massachusetts Institute Of Technology Himastatin derivatives, and processes of preparation thereof, and uses thereof

Citations (1)

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EP0276051A2 (fr) * 1987-01-06 1988-07-27 Arizona Board Of Regents Composés antinéoplastiques

Patent Citations (1)

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EP0276051A2 (fr) * 1987-01-06 1988-07-27 Arizona Board Of Regents Composés antinéoplastiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Experientia, vol. 45, 1989, Birkh{user Verlag, CH-4010, (Basel, CH), G.R. PETTIT et al.: "Isolation and structure of the strong cell growth and tubulin inhibitor combretastatin A-4", pages 209-211, see the whole document (cited in the application) *

Cited By (62)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5569786A (en) * 1987-01-06 1996-10-29 Arizona Board Of Regents Acting On Behalf Of Arizona State University Isolation, structural elucidation and synthesis of novel antineoplastic substances denominated "combretastatins"
WO1994005682A1 (fr) * 1992-08-31 1994-03-17 Francesca Pelizzoni Derives de combretastatine a activite antitumorale et leur procede de preparation
US5561122A (en) * 1994-12-22 1996-10-01 Arizona Board Of Regents Acting On Behalf Of Arizona State University Combretastatin A-4 prodrug
EP0731085A1 (fr) 1995-03-07 1996-09-11 Ajinomoto Co., Inc. Dérivés de stylbène et compositions pharmaceutiques les contenant
EP1045853A4 (fr) * 1998-01-09 2002-04-17 Univ Arizona State Synthese de promedicaments a base de combrestatine a-4 et de leurs trans-isomeres
US7557096B2 (en) 1998-01-09 2009-07-07 Arizona Board of Regents, a body corporate of the State of Arizona, acting for an on behalf of the Arizona State University Synthesis of combretastatin A-4 prodrugs and trans-isomers thereof
US7655696B2 (en) 1998-04-03 2010-02-02 Ajinomoto Co., Inc. Anti-tumor composition
US6992106B2 (en) 1998-04-03 2006-01-31 Ajinomoto Co., Inc. Anti-tumor composition
EP1068870A4 (fr) * 1998-04-03 2003-02-12 Ajinomoto Kk Agents antitumoraux
US7973076B2 (en) 1998-04-03 2011-07-05 Ajinomoto Co., Inc. Anti-tumor composition
JP2002537250A (ja) * 1999-02-16 2002-11-05 アンジオジーン ファーマスーティカルズ リミテッド 血管損傷活性での置換されたスチルベン化合物
US7265136B1 (en) 1999-02-16 2007-09-04 Angiogene Pharmaceuticals Ltd. Substituted stilbene compounds with vascular damaging activity
WO2000048590A1 (fr) * 1999-02-16 2000-08-24 Angiogene Pharmaceuticals Ltd. Composes de stilbene substitue ayant une activite de degradation vasculaire
EP2289521A3 (fr) * 1999-02-18 2011-10-05 Arizona Board Of Regents Compositions et procédé d'utilisation pour le ciblage de la destruction vasculaire
WO2001012579A3 (fr) * 1999-08-12 2001-10-11 Angiogene Pharm Ltd Nouveaux stilbenes a activite de degradation vasculaire
US7868047B2 (en) 1999-12-06 2011-01-11 Welichem Biotech Inc. Anti-inflammatory and psoriasis treatment and protein kinase inhibition by hydroxy stilbenes and novel stilbene derivatives and analogues
WO2001042231A3 (fr) * 1999-12-06 2001-11-01 Welichem Biotech Inc Traitement anti-inflammatoire et psoriasique et inhibition de la proteine kinase par des hydroxylstilbenes et de nouveaux derives de stilbene ou analogues
US7321050B2 (en) 1999-12-06 2008-01-22 Welichem Biotech Inc. Anti-inflammatory and psoriasis treatment and protein kinase inhibition by hydroxy stilbenes and novel stilbene derivatives and analogues
WO2001081355A1 (fr) * 2000-04-27 2001-11-01 Arizona Board Of Regents, A Body Corporate Of The State Of Arizona,Acting For And On Behalf Of Arizona State University Promedicaments a base de combretastatine a-1 phosphate et de combretastatine b-1 phosphate
US7078552B2 (en) 2000-04-27 2006-07-18 Arizona Board Of Regents Combretastatin A-1 phosphate and combretastatin B-1 phosphate prodrugs
US6743937B2 (en) 2000-07-17 2004-06-01 Oxigene, Inc. Efficient method of synthesizing combretastatin A-4 prodrugs
US7105501B2 (en) * 2000-08-15 2006-09-12 Angiogene Pharmaceuticals Ltd. Compositions with vascular damaging activity
US6670344B2 (en) 2000-09-14 2003-12-30 Bristol-Myers Squibb Company Combretastatin A-4 phosphate prodrug mono- and di-organic amine salts, mono- and di- amino acid salts, and mono- and di-amino acid ester salts
CN100338077C (zh) * 2000-09-14 2007-09-19 布里斯托-美尔斯奎比公司 康泼瑞素a－4磷酸前体药物单－和双－有机胺盐,单－和双－氨基酸盐,和单－和双－氨基酸酯盐
KR100858464B1 (ko) * 2000-09-14 2008-09-16 브리스톨-마이어스 스큅 컴퍼니 콤브레타스타틴 ａ-4 인산염 프로드럭 모노- 및 디-유기아민 염, 모노- 및 디-아미노산 염, 그리고 모노- 및디-아미노산 에스테르 염
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